Article

Acute Thrombogenicity of a Durable Polymer Everolimus-Eluting Stent Relative to Contemporary Drug-Eluting Stents With Biodegradable Polymer Coatings Assessed Ex Vivo in a Swine Shunt Model

August 2015
JACC Cardiovascular Interventions 8(9):1248-60

DOI:10.1016/j.jcin.2015.03.029

Source
PubMed

Authors:

Qi Cheng

CVPath Institute

Eduardo Acampado

CVPath Institute

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This study sought to evaluate whether the permanent fluoropolymer-coated Xience Xpedition everolimus-eluting stent (Xience-EES) exhibits lower acute thrombogenicity compared with contemporary drug-eluting stents (DES) with biodegradable polymer coatings in an acute swine shunt model. Previous pre-clinical and clinical experience suggests that several factors may influence the predisposition for acute thrombus formation of polymer-coated DES, including stent design and the polymer coating technology. It remains unclear whether relevant differences exist with respect to acute thrombogenicity, particularly between current commercial stent designs using permanent polymers and those using biodegradable polymers. An ex vivo carotid to jugular arteriovenous porcine shunt model involving a test circuit of 3 in-line stents, was used to test acute thrombogenicity, where Xience-EES (n = 24) was compared with 4 CE-marked DES with biodegradable polymer coatings (BioMatrix Flex, Synergy, Nobori, and Orsiro [n = 6 each]). After 1 h of circulation, platelet aggregation in whole mount stents was evaluated by confocal microscopy with immunofluorescent staining against dual platelet markers (CD61/CD42b) along with scanning electron microscopy. Xience-EES showed the least percentage of thrombus-occupied area as compared with the biodegradable polymer-coated DES, with a significant difference compared with BioMatrix Flex and Synergy (mean differences: [BioMatrix Flex: 15.54, 95% confidence interval [CI]: 11.34 to 19.75, p < 0.001; Synergy: 8.64, 95% CI: 4.43 to 12.84, p < 0.001; Nobori: 4.22, 95% CI: -0.06 to 8.49, p = 0.055; Orsiro: 2.95, 95% CI: -1.26 to 7.15, p = 0.286). The number of cell nuclei on strut surfaces was also the least in Xience-EES, with a significant difference relative to BioMatrix Flex, Nobori, and Orsiro (mean ratios: BioMatrix Flex: 4.73, 95% CI: 2.46 to 9.08, p < 0.001; Synergy: 1.44, 95% CI: 0.75 to 2.76, p = 0.51; Nobori: 5.97, 95% CI: 3.11 to 11.44, p < 0.001; Orsiro: 5.16, 95% CI: 2.69 to 9.91, p < 0.001). Xience-EES's overall design confers acute thromboresistance relative to contemporary DES with biodegradable coatings, with less platelet aggregation versus BioMatrix Flex and Synergy, and less inflammatory cell attachment versus BioMatrix Flex, Nobori, and Orsiro, in an ex vivo swine shunt model, which lends support to reported clinical findings of lower early stent thrombosis. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Overcoming challenges in refining the current generation of coronary stents

Article

Dec 2021

Introduction Late stent thrombosis caused by delayed vascular healing and prolonged local inflammation were major drawbacks of 1st generation drug-eluting stents (DES). Strut design, biocompatibility of polymer, and drug-release profiles were improved in 2nd and 3rd generation DES. Accordingly, the indications for percutaneous coronary intervention with DES have been expanded to more complex patients and lesions. Despite these improvements, significant barriers such as greater flexibility in the duration of dual-antiplatelet therapy (DAPT) as well as reducing long-term stent-related events remain. To achieve ideal short- and long-term results, these existing limitations need to be overcome. Areas covered We will discuss the current limitations of coronary DES and how they might be overcome from pathological and clinical viewpoints. Expert opinion Optimizing DAPT duration after stent implantation and prevention of in-stent neoatherosclerosis are two major issues in current DES. Overcoming these drawbacks is a prerequisite towards achieving better short- and long-term clinical outcomes. New technologies including platform design, polymer types, and anti-proliferative agent itself might lead to further improvements. Although the initial experience with bioresorbable scaffold/stents (BRS) was disappointing, positive results of clinical studies regarding novel BRS are raising expectations. Overall, further device innovation is desired for overcoming the limitations of current DES.

Early Vascular Response to Ultrathin Biodegradable Polymer Sirolimus-Eluting Stents for the Treatment of ST-Elevation Myocardial Infarction After Plaque Rupture

Article

Jan 2021

Recent clinical studies suggest that newer-generation drug-eluting stents that combine ultrathin struts and nanocoating (biodegradable polymer sirolimus-eluting stents, BP-SES) could improve long-term clinical outcomes in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). However, the early vascular response to BP-SES in these patients has not been investigated so far. We examined this response in 20 patients with STEMI caused by plaque rupture using frequency-domain optical coherence tomography (OCT) to understand the underlying mechanisms. Plaque rupture was diagnosed by OCT before PCI with BP-SES implantation was performed. OCT was again performed before the final angiography (post-PCI) and after 2 weeks (2W-OCT). BP-SES placement caused protrusion of atherothrombotic material into the stent lumen and incomplete stent apposition in all patients. After 2 weeks, incomplete stent apposition was significantly reduced (% malapposed struts: post-PCI 4.7 ± 3.3%; 2W-OCT 0.9 ± 1.2%; P < 0.0001), and the percentage of uncovered struts also significantly decreased (% uncovered struts: post-PCI; 69.8 ± 18.3%: 2W-OCT; 29.6 ± 11.0%, P < 0.0001). The maximum protrusion area of the atherothrombotic burden was significantly reduced (post-PCI 1.36 ± 0.70 mm²; 2W-OCT 0.98 ± 0.55 mm²; P = 0.004). This study on the early vascular responses following BP-SES implantation showed rapid resolution of atherothrombotic material and progression of strut apposition and coverage. (UMIN000041324)

Comparison of overexpansion capabilities and thrombogenicity at the side branch ostia after implantation of four different drug eluting stents

Article

Full-text available

Nov 2020

Interventions in bifurcation lesions often requires aggressive overexpansion of stent diameter in the setting of long tapering vessel segment. Overhanging struts in front of the side branch (SB) ostium are thought to act as a focal point for thrombi formation and consequently possible stent thrombosis. This study aimed to evaluate the overexpansion capabilities and thrombogenicity at the SB ostia after implantation of four latest generation drug-eluting stents (DES) in an in-vitro bifurcation model. Four clinically available modern DES were utilized: one bifurcation dedicated DES (Bioss LIM C) and three conventional DES (Ultimaster, Xience Sierra, Biomime). All devices were implanted in bifurcation models with proximal optimization ensuring expansion before perfusing with porcine blood. Optical coherence tomography (OCT), immunofluorescence (IF) and scanning electron microscope analysis were done to determine thrombogenicity and polymer coating integrity at the over-expanded part of the stents. Computational fluid dynamics (CFD) was performed to study the flow disruption. OCT (p = 0.113) and IF analysis (p = 0.007) demonstrated lowest thrombus area at SB ostia in bifurcation dedicated DES with favorable biomechanical properties compared to conventional DES. The bifurcated DES also resulted in reduced area of high shear rate and maximum shear rate in the CFD analysis. This study demonstrated numerical differences in terms of mechanical properties and acute thrombogenicity at SB ostia between tested devices.

Mid-term Clinical Outcomes of Immediate Protamine Use Following Elective Percutaneous Coronary Interventions

Article

Sep 2020
INT HEART J

Bleeding complication has been considered as a serious problem in current percutaneous coronary interventions (PCI). Fortunately, several groups have already reported the effectiveness of protamine use just after PCI to immediately remove any arterial sheath. However, there is a concern that protamine reversal may increase non-occlusive thrombus and, in turn, lead to mid-term cardiovascular events such as target vessel revascularization (TVR) or stent thrombosis. Thus, the purpose of this study was to evaluate whether protamine use following elective PCI was associated with mid-term clinical outcomes. In total, 472 patients were included in this study; subsequently, they were divided into protamine group (n = 142) and non-protamine group (n = 330). The primary endpoint was the composite of ischemia-driven TVR and stent thrombosis. The median follow-up period was determined to be at 562 days. In total, 32 primary endpoints were observed during the study period, and the incidence of primary endpoints tended to be greater in the protamine group than in the non-protamine group (P = 0.056). However, the lesion length, the degree of calcification, and the prevalence of hemodialysis were significantly determined greater in the protamine group than in the non-protamine group. In the multivariate Cox proportional hazards model, the use of protamine (versus non-protamine: hazard ratio 0.542 and 95% confidence interval 0.217-1.355, P = 0.191) was deemed not to be associated with the primary endpoint after controlling legion length, calcification, and hemodialysis. In conclusion, immediate protamine use following elective PCI did not increase mid-term ischemia-driven TVR or stent thrombosis. However, immediate protamine use after PCI should be discussed further for the safety of the patient.

Cut-off value of mal-apposition volume and depth for resolution at early phase of acute incomplete stent apposition after CoCr-EES implantation

Article

Full-text available

Nov 2019
INT J CARDIOVAS IMAG

The purpose of this study was to clarify a cut-off value for acute incomplete stent apposition (ISA) volume and maximum-depth to predict ISA resolution at 1- and 3-month follow-up in patients treated with cobalt–chromium everolimus-eluting stents. In total, 95 cases and 103 stents were registered in the MECHANISM-Elective sub-study. Acute ISA-volume was measured by the trapezoid rule. ISA resolution of cut-off value at 1- and 3-month was estimated by ISA-volume and maximum-depth using receiver operatorating characteristic curve analysis. The total number of analysed acute ISAs was 202 in the 1-month group and 225 in the 3-month group. A total of 123 ISAs at 1-month and a total of 169 ISAs at 3-month had been resolved. The cut-off value of ISA resolution by ISA-volume was 0.169 mm³ at 1-month (AUC: 0.725, sensitivity: 72.2%, specificity: 61.0%) and 0.295 mm³ at 3-month (AUC: 0.757, sensitivity: 75.0%, specificity: 60.4%). The cut-off value of ISA resolution by ISA maximum-depth demonstrated was 0.285 mm at 1-month (area under curve (AUC): 0.789, sensitivity: 70.9%, specificity: 69.9%) and 0.305 mm at 3-month (AUC: 0.663, sensitivity: 60.7%, specificity: 66.9%). Incidence of ISA resolution was significantly lower in combination with cut-off values of ISA-volume and maximum-depth (33%, p < 0.001, at 1-month; 56%, p = 0.003, at 3-month). Combining the cut-off value of ISA-volume with the maximum-depth might be helpful to consider the endpoint of the PCI procedure.

Anti-thrombogenic coatings for devices in neurointerventional surgery: Case report and review of the literature

Article

Full-text available

Jun 2019

Background Stent-assisted coiling and extra-saccular flow diversion require dual anti-platelet therapy due to the thrombogenic properties of the implants. While both methods are widely accepted, thromboembolic complications and the detrimental effects of dual anti-platelet therapy remain a concern. Anti-thrombogenic surface coatings aim to solve both of these issues. Current developments are discussed within the framework of an actual clinical case. Case description A 33-year-old male patient lost consciousness while doing sport and was administered 500 mg acetylsalicylic acid on site. Computed tomography revealed a massive subarachnoid haemorrhage, and digital subtraction angiography showed an aneurysm of the right middle cerebral artery. Stent-assisted coiling using a neck bridging device with a hydrophilic coating (pCONUS_HPC) was considered as an appropriate approach. Another 500 mg acetylsalicylic acid IV was given. After the single anti-platelet therapy was seen to be effective, a pCONUS_HPC was implanted, and the aneurysm sac subsequently fully occluded using coils. No thrombus formation was encountered. During the following days, 2 × 500 mg acetylsalicylic acid IV daily were required to maintain single anti-platelet therapy, monitored by frequent response testing. Follow-up digital subtraction angiography after 13 days confirmed the occlusion of the aneurysm and the patency of the middle cerebral artery. Conclusion A variety of ways to reduce the thrombogenicity of neurovascular stents is discussed. Hydrophilic surface coatings are a valid concept to improve the haemocompatibility of neurovascular implants while avoiding the use of dual anti-platelet therapy. Phosphorylcholine and phenox hydrophilic polymer coating are currently the most promising candidates. This concept is supported by anecdotal experience. However, formalised registries and randomised trials are currently being established.

A novel polymer-free everolimus-eluting stent with a nitrogen-doped titanium dioxide film inhibits restenosis and thrombosis in a swine coronary model

Article

Feb 2023

Background: Short-term outcomes regarding the safety and efficacy of a polymer-free everolimus-eluting stent (EES) with a nitrogen-doped titanium dioxide (N-TiO₂) film in a swine coronary model have been reported. However, the long-term results of the use of this type of stent have not yet been evaluated or compared to those of other polymer-free coronary stents. Therefore, this study aimed to determine the mid- to long-term safety and efficacy of a polymer-free EES with an N-TiO₂ film in a swine coronary model. Methods: Polymer-free EES with N-TiO₂ films (n = 30) and polymer-free sirolimus-eluting stents (SES; n = 30) were implanted in 30 pigs. Quantitative coronary analysis and optical coherence tomography were conducted immediately and at 1 (quantitative coronary analysis only), 3, and 6 months after stenting. Histopathologic examinations were performed at 1, 3, and 6 months after stenting. Results: The polymer-free EES group had a lower percentage of neointimal growth than the polymer-free SES group at 3 months (22.5% ± 11.4% vs. 32.1% ± 12.3%; p < 0.001). The polymer-free EES group had a lower fibrin score than the polymer-free SES group at 1 month (1.9 ± 0.45 vs. 2.5 ± 0.54; p = 0.001). The re-endothelialization rates were similar between groups. The polymer-free EES group had a lower percentage of the area of stenosis than the polymer-free SES group throughout the follow-up period. Conclusions: The novel polymer-free EES with an N-TiO₂ film has superior safety and efficacy than the polymer-free SES at the 6-month follow-up in a swine model.

The emerging role of adopting protamine for reducing the risk of bleeding complications during the percutaneous coronary intervention: A meta‐analysis

Article

Full-text available

Nov 2022
J CARDIAC SURG

Background The safety and the benefits of reducing the risk of bleeding complications via protamine administration during the percutaneous coronary intervention (PCI) remains unclear. This study aimed to systematically assessed the efficacy and safety of using protamine in PCI. Method Potential academic studies were identified from PubMed, Cochrane Library, EMBASE, and Web of Science. The time range we retrieved from was that from the inception of electronic databases to March 31, 2022. Gray studies were identified from the references of included literature reports. Stata version 12.0 statistical software (StataCorp LP) was used to analyze the pooled data. Results A total of seven studies were involved in our study. The overall participants of the protamine group were 4983, whereas it was 1953 in the nonprotamine group. This meta‐analysis indicated that protamine was preferable for PCI as its lower value of major bleeding (odds ratio [OR] = 0.489, 95% confidence interval [CI]: 0.362–0.661, p < .001) and minor bleeding (OR = 0.281, 95% CI: 0.123–0.643, p = .003). Additionally, the protamine did not tend to be related a higher incidence of mortality (p = .143), myocardial infarction (p = .990), and stent thrombosis (p = .698). Conclusions Based on available evidence, use of protamine may reduce the risk of bleeding complications without increasing the risk of mortality, myocardial infarction, and stent thrombosis. Given the relevant possible biases in our study, adequately powered and better‐designed studies with long‐term follow‐up are required to reach a firmer conclusion.

Polymer Coating Integrity, Thrombogenicity and Computational Fluid Dynamics Analysis of Provisional Stenting Technique in the Left Main Bifurcation Setting: Insights from an In-Vitro Model

Article

Full-text available

Apr 2022

Currently, the provisional stenting technique is the gold standard in revascularization of lesions located in the left main (LM) bifurcation. The benefit of the routine kissing balloon technique (KBI) in bifurcation lesions is still debated, particularly following the single stent treatment. We compared the latest-generation drug-eluting stent (DES) with no side branch (SB) dilatation “keep it open” technique (KIO) vs. KBI technique vs. bifurcation dedicated drug-eluting stent (BD-DES) implantation. In vitro testing was performed under a static condition in bifurcation silicone vessel models. All the devices were implanted in accordance with the manufacturers’ recommendations. As a result, computational fluid dynamics (CFD) analysis demonstrated a statistically higher area of high shear rate in the KIO group when compared to KBI. Likewise, the maximal shear rate was higher in number in the KIO group. Floating strut count based on the OCT imaging was significantly higher in KIO than in KBI and BD-DES. Furthermore, according to OTC analysis, the thrombus area was numerically higher in both KIO and KBI than in the BD-DES. Scanning electron microscopy (SEM) analysis shows the highest degree of strut coating damage in the KBI group. This model demonstrated significant differences in CFD analysis at SB ostia with and without KBI optimization in the LM setting. The adoption of KBI was related to a meaningful reduction of flow disturbances in conventional DES and achieved results similar to BD-DES.

COBRA PzF™ coronary stent in clinical and preclinical studies: setting the stage for new antithrombotic strategies?

Article

Full-text available

Sep 2021

Major advances have been made in coronary artery stent technology over the last decades. Drug-eluting stents reduced in-stent restenosis and have shown better outcomes compared with bare metal stents, yet some limitations still exist to their use. Because they delay healing of the vessel wall, longer dual antiplatelet therapy is mandatory to mitigate against stent thrombosis and this limitation is most concerning in subjects at high risk for bleeding. The COBRA PzF nanocoated coronary stent has been associated with accelerated endothelialization relative to drug-eluting stents, reduced inflammation and thromboresistance in preclinical studies, suggesting more flexible dual antiplatelet therapy requirement with potential benefits especially in those at high bleeding risk. Here, we discuss the significance of COBRA PzF in light of recent experimental and clinical studies.

Factors Influencing 1st and 2nd Generation Drug-Eluting Stent Performance: Understanding the Basic Pharmaceutical Drug-in-Polymer Formulation Factors Contributing to Stent Thrombosis Do We Really Need to Eliminate the Polymer?

Article

Full-text available

Sep 2021
J PHARM PHARM SCI

Iva Srdanovic

Drug-eluting stents (DES) have a major role in treating cardiovascular disease. The evolution of bare metal stents into 1st generation durable-polymer DES (DP-DES) reduced the rate of in-stent restenosis (ISR) and the need for repeat-revascularization. However, clinical outcomes showed similar rates of late stent thrombosis (ST<1 year) and higher rates of very late stent thrombosis (ST>1 year) necessitating the advent of 2nd generation more biocompatible polymer DES and biodegradable-polymer DES (BP-DES) that reduced ST rates with shorter dual anti-platelet therapy (DAPT). Despite the improvements in drugs and polymer biocompatibility for both durable and biodegradable polymers, stent thrombosis remains an issue. Doubts remain about the safety and efficacy of the more biocompatible 2nd generation durable polymers in respect to vessel inflammatory and thrombogenic response as compared to biodegradable polymers despite clinical trial and meta-analyses evidence indicating that 2nd generation DP-DES are non-inferior to BP-DES for stent thrombosis. A long-term presence of the polymer can cause inflammation and thrombogenesis. However, the cause of stent thrombosis is multi-factorial from a drug-in-polymer formulation perspective; e.g., drug release kinetics, drug physiochemical and pharmacological properties, degradation kinetics; polymer biocompatibility and hemocompatibility and coating properties. It appears that the focus should be on controlling burst release and developing more biocompatible, durable polymers, especially considering the cost of PCI utilizing biodegradable, polymer-free and bioresorbable scaffolds. This may give an insight into certain DP-DES effectiveness as compared to BP-DES for the existing clinical data and improve future stent development.

Early Vascular Healing Following Bioresorbable-Polymer Sirolimus-Eluting Stent Placement Compared to That with Durable-Polymer Everolimus-Eluting Stent: Sequential Optical Coherence Tomography Study

Article

May 2021

A recent thinner strut drug-eluting stent might facilitate early strut coverage after its placement. We aimed to investigate early vascular healing responses after the placement of an ultrathin-strut bioresorbable-polymer sirolimus-eluting stent (BP-SES) compared to those with a durable-polymer everolimus-eluting stent (DP-EES) using optical coherence tomography (OCT) imaging. This study included 40 patients with chronic coronary syndrome (CCS) who underwent OCT-guided percutaneous coronary intervention (PCI). Twenty patients each received either BP-SES or DP-EES implantation. OCT was performed immediately after stent placement (baseline) and at 1-month follow-up. At one month, the percentage of uncovered struts reduced significantly in both the BP-SES (80.9 ± 10.3% to 2.9 ± 1.7%; P < 0.001) and DP-EES (81.9 ± 13.0% to 5.7 ± 1.8%; P < 0.001) groups, and the percentage was lower in the BP-SES group than in the DP-EES group (P < 0.001). In the BP-SES group, the percentage of malapposed struts also decreased significantly at 1 month (4.9 ± 3.7% to 2.6 ± 3.0%; P = 0.025), which was comparable to that of the DP-EES group (2.5 ± 2.2%; P = 0.860). The optimal cut-off value of the distance between the strut and vessel surface immediately after the placement to predict resolved malapposed struts was ≤ 160 μm for BP-SES and ≤ 190 μm for DP-EES. Compared to DP-EES, ultrathin-strut BP-SES demonstrated favorable vascular responses at one month, with a lower rate of uncovered struts and a comparable rate of malapposed struts.

Effect of Prostanoids on Human Platelet Function: An Overview

Article

Full-text available

Dec 2020
INT J MOL SCI

Prostanoids are bioactive lipid mediators and take part in many physiological and pathophysiological processes in practically every organ, tissue and cell, including the vascular, renal, gastrointestinal and reproductive systems. In this review, we focus on their influence on platelets, which are key elements in thrombosis and hemostasis. The function of platelets is influenced by mediators in the blood and the vascular wall. Activated platelets aggregate and release bioactive substances, thereby activating further neighbored platelets, which finally can lead to the formation of thrombi. Prostanoids regulate the function of blood platelets by both activating or inhibiting and so are involved in hemostasis. Each prostanoid has a unique activity profile and, thus, a specific profile of action. This article reviews the effects of the following prostanoids: prostaglandin-D2 (PGD2 ), prostaglandin-E1,-E2 and E3 (PGE1, PGE2, PGE3 ), prostaglandin F2α (PGF2α ), prostacyclin (PGI2 ) and thromboxane-A2 (TXA2 ) on platelet activation and aggregation via their respective receptors.

Histopathologic response after hydrophilic polyethylene glycol-coating stent and hydrophobic octadecylthiol-coating stent implantations in porcine coronary restenosis model

Article

Full-text available

Dec 2020
J MATER SCI-MATER M

Device-related problems of drug-eluting stents, including stent thrombosis related to antiproliferative drugs and polymers, can cause adverse events such as inflammation and neointimal hyperplasia. Stent surface modification, wherein the drug and polymer are not required, may overcome these problems. We developed hydrophilic polyethylene glycol (PEG)-coating and hydrophobic octadecylthiol (ODT)-coating stents without a drug and polymer and evaluated their histopathologic response in a porcine coronary restenosis model. PEG-coating stents (n = 12), bare-metal stents (BMS) (n = 12), and ODT-coating stents (n = 10) were implanted with oversizing in 34 porcine coronary arteries. Four weeks later, the histopathologic response, arterial injury, inflammation, and fibrin scores were analyzed. A p value < 0.05 was considered statistically significant. There were significant differences in the internal elastic lamina area, lumen area, neointimal area, percent area of stenosis, arterial injury score, inflammation score, and fibrin score among the groups. Compared to the BMS or ODT-coating stent group, the PEG-coating stent group had significantly increased internal elastic lamina and lumen area (all p < 0.001) and decreased neointimal area and percent area of stenosis (BMS: p = 0.03 and p < 0.001, respectively; ODT-coating: p = 0.013 and p < 0.001, respectively). Similarly, the PEG-coating group showed significantly lower inflammation and fibrin scores than the BMS or ODT-coating groups (BMS: p = 0.013 and p = 0.007, respectively; ODT-coating: p = 0.014 and p = 0.008, respectively). In conclusion, hydrophilic PEG-coating stent implantation was associated with lower inflammatory response, decreased fibrin deposition, and reduced neointimal hyperplasia than BMS or hydrophobic ODT-coating stent implantation in the porcine coronary restenosis model.

Vascular Response Occurring at 3 Months After Everolimus-Eluting Cobalt-Chromium Stent Implantation in Patients With ST-Segment Elevation Myocardial Infarction vs. Stable Coronary Artery Disease

Article

Full-text available

Oct 2020
CIRC J

Background: Second-generation drug-eluting stents (DES) reduce the incidence of stent thrombosis, even in patients with ST-segment elevated myocardial infarction (STEMI). However, the early local vascular healing after DES implantation in STEMI lesions, which mainly concerns stent thrombosis, is still unclear.Methods and Results:We attempted to determine early local vascular healing 3 months after cobalt-chromium everolimus-eluting stent (CoCr-EES) implantation in STEMI lesions relative to stable coronary artery disease (CAD) lesions. This prospective, multicenter study analyzed 96 total lesions (STEMI=49, stable CAD=51) by frequency domain-optical coherence tomography (FD-OCT) performed post-procedure and at the 3-month follow-up. Although CoCr-EES implanted in STEMI were almost entirely covered at 3 months, they had a relatively high incidence of uncovered struts compared with stable CAD (5.5% vs. 1.6%, P<0.001). Intrastent thrombus in the 2 groups was primarily resolved at the 3-month follow-up (STEMI: 91.7%→26.5%, stable CAD: 74.5%→11.8%). Regarding irregular protrusion, complete resolution was observed in stable CAD (21.6%→0%), while a few stents remained in STEMI (79.2%→8.2%). Although there were almost no changes for the serial change of average lumen area in STEMI, there were slight but significant decreases in stable CAD [STEMI 0.08 (-0.44, 0.55) mm2, stable CAD -0.35 (-0.55, 0.11) mm2; P=0.009]. Conclusions: Although strut coverage after CoCr-EES implantation for STEMI lesions was slightly delayed, the healing process appeared to be acceptable in both STEMI and stable CAD.

Early thrombogenicity of coronary stents: comparison of bioresorbable polymer sirolimus-eluting and bare metal stents in an aortic rat model

Article

Jun 2020

Background: Although 1-month dual antiplatelet therapy (DAPT) in patients treated with bare metal stents (BMS) is well established, the optimal duration of DAPT after implantation of a drug-eluting stent (DES) is still a matter of debate. The safety of shortened DAPT is under investigation due to concern about the risk of stent thrombosis. Data on platelet activation and prothrombotic response in vivo following bioresorbable polymer sirolimus-eluting stent (BP-SES) implantation are scarce. Objectives: The aim of our study was to compare the early thrombogenicity of BP-SES with that of BMS in an aortic rat model. Methods and results: Overall, 30 rats underwent stent implantation in the abdominal aorta: BMS (Pro-Kinetic Energy; N=15) and BP-SES (Ultimaster Tansei; N=15) were compared in terms of their early thrombogenicity. CD62P exposure at the platelet surface and fibrinogen binding at the integrin receptor were not different between BMS and BP-SES over time. The thrombus coverage of the scaffold (0 vs. 0.1%, P=0.84) was similarly low in both groups at Day 28; thrombotic deposits had totally disappeared at Day 84. The endothelial strut coverage was similarly high at 1 month (90 vs. 95%, P=0.64) and 3 months (87 vs. 97%, P=0.99) following BMS and BP-SES implantation, respectively. Conclusions: This study demonstrates the low early thrombogenicity of a BP-SES implanted in an aortic rat model, which did not differ from a BMS. These data could be helpful to support the safety of a shortened 1-month DAPT duration following BP-SES implantation in the human coronary artery.

Early scaffold strut coverage in ultra-high molecular weight amorphous PLLA sirolimus-eluting bioresorbable scaffolds: Impact of strut thickness assessed in normal porcine coronary arteries

Article

Full-text available

Mar 2020
POSTEP KARDIOL INTER

A Review of the Ultrathin Orsiro Biodegradable Polymer Drug-eluting Stent in the Treatment of Coronary Artery Disease

Article

Full-text available

Dec 2019

Drug-eluting stents (DES) have revolutionised the treatment of coronary artery disease (CAD) in patients undergoing percutaneous coronary intervention. In recent years, there has been a focus on a new generation of DES, such as biodegradable polymer DES (BP-DES). This novel stent platform was developed with the hope of eliminating the risk of very late stent thrombosis associated with the current gold-standard durable polymer DES (DP-DES). Ultrathin Orsiro BP-DES (Biotronik, Bülach, Switzerland) are based on a cobalt-chromium stent platform that is coated with a bioresorbable polymer coating containing sirolimus. These devices have one of the thinnest struts available in the current market and have the theoretical benefit of reducing a chronic inflammatory response in the vessel wall. In 2019, the United States Food and Drug Administration (FDA) approved the use of Orsiro BP-DES in patients with CAD based on promising results in recent landmark trials, such as BIOFLOW V and BIOSTEMI. The aim of the present review article was to discuss the history of stent technology and the continued opportunities for improvements, focusing on the potential benefits of Orsiro BP-DES.

Vascular responses to coronary calcification following implantation of newer-generation drug-eluting stents in humans: Impact on healing

Article

Dec 2019
EUR HEART J

Aims: Vascular calcification is routinely encountered in percutaneous coronary intervention (PCI) and severe coronary calcification is a known predictor of in-stent restenosis and stent thrombosis. However, the histopathologic mechanisms behind such events have not been systematically described. Methods and results: From our registry of 1211 stents, a total of 134 newer-generation drug-eluting stents (DES) (Xience, Resolute-Integrity, PROMUS-Element, and Synergy) with duration of implant ≥30 days were histologically analysed. The extent of calcification of the stented lesions was evaluated radiographically and divided into severe (SC, n = 46) and non-severely calcified lesions (NC, n = 88). The percent-uncovered struts per section {SC vs. NC; median 2.4 [interquartile range (IQR) 0.0-19.0] % vs. 0.0 (IQR 0.0-4.6) %, P = 0.02} and the presence of severe medial tears (MTs) (59% vs. 44%, respectively, P = 0.03) were greater in SC than NC. In addition, SC had a higher prevalence of ≥3 consecutive struts lying directly in contact with surface calcified area (3SC) (52% vs. 8%, respectively, P < 0.0001). Multivariate analysis demonstrated that sections with duration of implantation ≤6 months [odds ratio (OR): 7.7, P < 0.0001], 3SC (OR: 6.5, P < 0.0001), strut malapposition (OR: 5.0, P < 0.0001), and lack of MTs (OR: 2.5, P = 0.0005) were independent predictors of uncovered struts. Prevalence of neoatherosclerosis was significantly lower in SC than that of NC (24% vs. 44%, P = 0.02). Conclusion: Severe calcification, especially surface calcified area is an independent predictor of uncovered struts and delayed healing after newer-generation DES implantation. These data expand of knowledge of the vascular responses of stenting of calcified arteries and suggests further understand of how best to deal with calcification in patients undergoing PCI.

In vitro thrombogenicity of drug-eluting and bare metal stents

Article

Nov 2019
THROMB RES

Aims: We sought to investigate the thrombogenicity of different DES and BMS in an in vitro system of stent perfusion. Material and methods: The experimental model consisted of a peristaltic pump connected to 4 parallel silicone tubes in which different stents were deployed. Blood was drawn from healthy volunteers and the amount of stent surfaced-induced thrombus deposition was determined using 125I-fibrinogen. Results: Compared to Resolute, Biomatrix and Vision, Xience was associated with the lowest amount of stent surface-induced thrombus formation, with a significant difference compared to Vision (125I-fibrinogen median value deposition [IQ range]: 50 ng [25-98] versus 560 ng [320-1520], respectively, p < 0.05), but not to other DES. In the second set of experiments Fluoropolymer-coated BMS not eluting drug was associated with a significant 3-fold reduction in 125I-fibrinogen deposition (245 ng [80-300]) compared to Vision (625 ng [320-760], p < 0.05), but a 7-fold increase compared to Xience (35 ng [20-60], p < 0.05). Finally Xience was associated with a significantly greater absorption of albumin compared to BMS. Conclusions: In an in vitro system of stent perfusion, Xience was associated with the lowest amount of stent surface-induced thrombus formation compared with Resolute, Biomatrix and Vision, with a noted synergistic effect between the fluoropolymer and the drug.

Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial

Article

Jun 2019

Importance Very short mandatory dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with a drug-eluting stent may be an attractive option. Objective To test the hypothesis of noninferiority of 1 month of DAPT compared with standard 12 months of DAPT for a composite end point of cardiovascular and bleeding events. Design, Setting, and Participants Multicenter, open-label, randomized clinical trial enrolling 3045 patients who underwent PCI at 90 hospitals in Japan from December 2015 through December 2017. Final 1-year clinical follow-up was completed in January 2019. Interventions Patients were randomized either to 1 month of DAPT followed by clopidogrel monotherapy (n=1523) or to 12 months of DAPT with aspirin and clopidogrel (n=1522). Main Outcomes and Measures The primary end point was a composite of cardiovascular death, myocardial infarction (MI), ischemic or hemorrhagic stroke, definite stent thrombosis, or major or minor bleeding at 12 months, with a relative noninferiority margin of 50%. The major secondary cardiovascular end point was a composite of cardiovascular death, MI, ischemic or hemorrhagic stroke, or definite stent thrombosis and the major secondary bleeding end point was major or minor bleeding. Results Among 3045 patients randomized, 36 withdrew consent; of 3009 remaining, 2974 (99%) completed the trial. One-month DAPT was both noninferior and superior to 12-month DAPT for the primary end point, occurring in 2.36% with 1-month DAPT and 3.70% with 12-month DAPT (absolute difference, −1.34% [95% CI, −2.57% to −0.11%]; hazard ratio [HR], 0.64 [95% CI, 0.42-0.98]), meeting criteria for noninferiority (P < .001) and for superiority (P = .04). The major secondary cardiovascular end point occurred in 1.96% with 1-month DAPT and 2.51% with 12-month DAPT (absolute difference, −0.55% [95% CI, −1.62% to 0.52%]; HR, 0.79 [95% CI, 0.49-1.29]), meeting criteria for noninferiority (P = .005) but not for superiority (P = .34). The major secondary bleeding end point occurred in 0.41% with 1-month DAPT and 1.54% with 12-month DAPT (absolute difference, −1.13% [95% CI, −1.84% to −0.42%]; HR, 0.26 [95% CI, 0.11-0.64]; P = .004 for superiority). Conclusions and Relevance Among patients undergoing PCI, 1 month of DAPT followed by clopidogrel monotherapy, compared with 12 months of DAPT with aspirin and clopidogrel, resulted in a significantly lower rate of a composite of cardiovascular and bleeding events, meeting criteria for both noninferiority and superiority. These findings suggest that a shorter duration of DAPT may provide benefit, although given study limitations, additional research is needed in other populations. Trial Registration ClinicalTrials.gov Identifier: NCT02619760

Enhanced Thromboresistance and Endothelialization of a Novel Fluoropolymer-Coated Left Atrial Appendage Closure Device

Article

May 2023

Background: Device-related thrombus (DRT) after left atrial appendage closure (LAAC) procedures is a rare but potentially serious event. Thrombogenicity and delayed endothelialization play a role in the development of DRT. Fluorinated polymers are known to have thromboresistant properties that may favorably modulate the healing response to an LAAC device. Objectives: The goal of this study was to compare the thrombogenicity and endothelial coverage (EC) after LAAC between the conventional uncoated WATCHMAN FLX (WM) and a novel fluoropolymer-coated WATCHMAN FLX (FP-WM). Methods: Canines were randomized for implantation with WM or FP-WM devices and given no postimplant antithrombotic/antiplatelet agents. The presence of DRT was monitored by using transesophageal echocardiography and verified histologically. The biochemical mechanisms associated with coating were assessed by using flow loop experiments to quantify albumin adsorption, platelet adhesion, and porcine implants to quantify EC and the expression of markers of endothelial maturation (ie, vascular endothelial-cadherin/p120-catenin). Results: Canines implanted with FP-WM exhibited significantly less DRT at 45 days than those implanted with WM (0% vs 50%; P < 0.05). In vitro experiments showed significantly greater albumin adsorption (52.8 [41.0-58.3] mm2 vs 20.6 [17.2-26.6] mm2; P = 0.03) and significantly less platelet adhesion (44.7% [27.2%-60.2%] vs 60.9% [39.9%-70.1%]; P < 0.01) on FP-WM. Porcine implants showed significantly greater EC by scanning electron microscopy (87.7% [83.4%-92.3%] vs 68.2% [47.6%-72.8%]; P = 0.03), and higher vascular endothelial-cadherin/p120-catenin expression after 3 months on FP-WM compared with WM. Conclusions: The FP-WM device showed significantly less thrombus and reduced inflammation in a challenging canine model. Mechanistic studies indicated that the fluoropolymer-coated device binds more albumin, leading to reduced platelet binding, less inflammation, and greater EC.

Early vascular responses to abluminal biodegradable polymer-coated versus circumferential durable polymer-coated newer-generation drug-eluting stents in humans: a pathological study

Article

Nov 2022

Background: Recent clinical studies are testing strategies for short (1-3 months) dual antiplatelet therapy following newer-generation drug-eluting stent (DES) placement. However, detailed biological responses to newer-generation DES remain unknown in humans. Aims: We sought to evaluate early pathologic responses to abluminal biodegradable polymer-coated (BP-) DES compared with circumferential durable polymer-coated (DP-) DES in human autopsy cases. Methods: The study included 38 coronary lesions with newer-generation DES implanted for <90 days (DP-DES=24, BP-DES=14) in 26 autopsy cases. The degree of strut coverage was defined as follows: grade 0 (bare), grade 1 (with fibrin or tissues/cells without endothelium), grade 2 (with single-layered endothelium), and grade 3 (with endothelium and underlying smooth muscle cell layers). Results: The duration following implantation was similar in DP- and BP-DES (median=20 vs 17 days). A total of 2,022 struts (DP-DES=1,297, BP-DES=725) were pathologically analysed. Focal grade 2 coverage was observed as early as 5 days after the implantation in both stents. The multilevel mixed-effects ordered logistic regression model demonstrated that BP-DES exhibited greater strut coverage compared with DP-DES (odds ratio [OR]: 3.64, 95% confidence interval [CI]: 1.37-9.67; p=0.009), which remained significant after adjustment for the duration following implantation and underlying tissue characteristics (OR: 2.74, 95% CI: 1.10-6.80; p=0.030). The predictive probability of grade 2 and 3 coverage was comparably limited at 30 days (DP-DES=17.1%, BP-DES=28.7%) and increased at 90 days (DP-DES=76.5%, BP-DES=86.6%). Both stents showed low inflammation and a similar degree of fibrin deposition. Conclusions: Single-layered endothelial coverage begins in the days after newer-generation DES placement, and BP-DES potentially exhibit faster strut coverage with smooth muscle cell infiltration than DP-DES in humans. Nevertheless, vessel healing remains suboptimal in both stents at 30 days.

Dual strengthened corrosion control of biodegradable coating on magnesium alloy for vascular stent application

Article

Jan 2023
PROG ORG COAT

Recently, magnesium alloy vascular stents have aroused great attraction because of their biodegradability and good mechanical properties. However, the rapid degradation of magnesium alloy stents causes their premature collapse in clinical application. So far, there have been few magnesium alloy stent systems that achieved sufficient support time by using biodegradable coating. In this paper, a dual strengthened biodegradable coating on a AZ31b magnesium alloy stent was suggested to achieve stronger adhesion and lower water permeability. The composite coating consisted of a magnesium hydrate - magnesium fluoride (Mg(OH)2-MgF2) inorganic base layer constructed by a simple two-step solution immersion and a graphene oxide - poly(trimethylene carbonate) outer layer prepared by ultrasonic spraying. The biodegradable composite coating modified magnesium alloy exhibited an extremely low corrosion current density of 4.3 × 10⁻¹⁰ A·cm⁻², which is five orders of magnitude lower than the unmodified magnesium alloy. In vitro immersion tests revealed that the modification can effectively reduce the corrosion rate of the magnesium alloy stent, and the modified magnesium alloy stent can support at least 8 weeks. Furthermore, in vitro biological experiment revealed the modification of the composite coating improved the biocompatibility and ensured good microenvironment for vascular repair. These results suggest that the biodegradable composite coating has great potential for application in vascular stent.

Durable polymer versus biodegradable polymer drug-eluting stents in patients with acute coronary syndrome undergoing complex percutaneous coronary intervention: a post hoc analysis of the HOST-REDUCE-POLYTECH-ACS trial

Article

Aug 2022

Background: Comparative data of durable polymer (DP) versus biodegradable polymer (BP) drug-eluting stents (DES) are limited in patients presenting with acute coronary syndrome (ACS) undergoing complex percutaneous coronary intervention (PCI). Aims: We sought to evaluate the efficacy and safety of DP-DES and BP-DES in ACS patients receiving complex PCI. Methods: This study was a post hoc analysis of the HOST-REDUCE-POLYTECH-ACS trial. ACS patients were randomly assigned 1:1 to DP-DES or BP-DES in the HOST-REDUCE-POLYTECH-ACS trial. Complex PCI was defined as having at least 1 of the following features: ≥3 stents implanted, ≥3 lesions treated, total stent length ≥60 mm, bifurcation PCI with 2 stents, left main PCI, or heavy calcification. Patient-oriented (POCO, a composite of all-cause death, non-fatal myocardial infarction, and any repeat revascularisation) and device-oriented composite outcomes (DOCO, a composite of cardiac death, target vessel myocardial infarction, or target lesion revascularisation) were evaluated at 12 months. Results: Among 3,301 patients for whom full procedural data were available, 1,140 patients received complex PCI. Complex PCI was associated with higher risks of POCO and DOCO. The risks of POCO were comparable between DP-DES and BP-DES in both the complex (HR 0.87, 95% confidence interval [CI]: 0.57-1.33; p=0.522) and non-complex (HR 0.83, 95% CI: 0.56-1.24; p=0.368; p for interaction=0.884) PCI groups. DOCO was also not significantly different between DP-DES and BP-DES in both the complex (HR 0.74, 95% CI: 0.43-1.27; p=0.278) and non-complex (HR 0.67, 95% CI: 0.38-1.19; p=0.175; p for interaction=0.814) PCI groups. Conclusions: In ACS patients, DP-DES and BP-DES showed similar clinical outcomes irrespective of PCI complexity. The registration information for the HOST-REDUCE-POLYTECH-ACS trial is available at ClinicalTrials.gov: NCT02193971.

Recent Advances in Stent Technology: Do They Reduce Cardiovascular Events?

Article

Full-text available

Sep 2022
Curr Atherosclerosis Rep

Purpose of review: Drug-eluting stents are used in nearly all cases of percutaneous coronary revascularization and have been shown to be superior to balloon angioplasty or bare metal stents. The designs of these stents are continually evolving to maximize efficacy and safety. Recent findings: This review outlines the important components of a drug-eluting stent and highlights the changes in stent design that have led to the optimization of clinical outcomes. Most stents used in contemporary times are thin strut, durable polymer drug-eluting stents (DES) that elute either everolimus or zotarolimus. Newer DES designs incorporating bioresorbable polymers or ultrathin struts have shown encouraging safety and efficacy profiles. DES are essential for the management of patients with obstructive coronary artery disease and are used in most coronary interventions. Changes in stent designs over the past 30 years reflect the ongoing need to address the limitations of earlier stents aimed to improve patient outcomes.

Optical coherence tomography assessment of acute thrombogenicity at bifurcation sites using different stenting techniques: A porcine arteriovenous shunt study

Article

Apr 2022

Objectives: We aimed to compare bare-metal stents (BMS), durable-polymer everolimus-eluting stents (DP-EES), and abluminal biodegradable-polymer sirolimus-eluting stents (ABP-SES) in the bifurcation model setup. Background: The mechanism of thrombogenicity, which differs among second-generation stents implanted using double-kissing (DK) crush or culotte stenting techniques, remains unclear. We have shown previously that setting up a porcine arteriovenous shunt model is feasible and useful to assess thrombogenicity at vessel bifurcation points. Methods: Six porcine shunt models were prepared for the comparison between DK crush and culotte stenting techniques using BMS, DP-EES, and ABP-SES. Intracoronary imaging with high-resolution optical coherence tomography (OCT) was performed to evaluate the thrombogenicity in different stent types in the bifurcation stenting model and was evaluated by a core lab. Results: Culotte stenting demonstrated more thrombogenicity at the proximal main branch (MB) with DP-EES, side branch (SB) with BMS, and the bifurcation site irrespective of the stent type, while DK crush technique exhibited thrombogenicity only at SB with BMS and ABP-SES. OCT analysis revealed malapposition of DP-EES in the proximal MB with culotte stenting. Stent expansion was generally larger in ABP-SES than BMS and DP-EES. Conclusions: The study provides hypothesis-generating findings in distinct thrombogenicity of bifurcation stenting with DP- or ABP-coated drug-eluting stents.

Maintained P2Y12 inhibitor monotherapy after shorter‐duration of dual antiplatelet therapy in patients undergoing coronary drug‐eluting stents implantation: An updated meta‐analysis of randomized trials

Article

Feb 2022

What is known and objective: It is well known that high in-stent thrombotic risk due to the superimposition of a platelet-rich thrombus was considered as the main origin of major adverse cardiac events after stent implantation. The clinical management of antiplatelet therapy strategy after percutaneous coronary intervention (PCI) remains controversial. This study is sought to explore the efficacy and safety of a maintained P2Y12 inhibitor monotherapy after shorter-duration of dual antiplatelet therapy (DAPT) in these patients. Methods: Medline, Google Scholar, Web of Science, and the Cochrane Controlled Trials Registry were searched online for retrieving eligible citations. A composite of all-cause death, myocardial infarction (MI) and stroke was defined as major adverse cardio- and cerebro-vascular events (MACCE), which is analysed as the primary efficacy endpoint. The risk of bleeding events was chosen as safety endpoint. Results: Five randomized clinical trials (RCT) with 32,143 patients were finally analysed. A maintained P2Y12 inhibitor monotherapy after shorter-duration of DAPT cloud not only reduce the incidence of MACCE [odds ratios (OR): 0.89, 95% confidence intervals (CI): 0.79-0.99, p = 0.037], but also the bleeding risk (OR 0.61, 95% CI: 0.44-0.85, p = 0.003). No higher incidence of any ischaemic events, including MI, stroke or definite stent thrombosis (ST) was observed with respect to this new antiplatelet therapy option. Conclusions: A maintained P2Y12 inhibitor monotherapy after shorter-duration of DAPT was suggested as a more preferable antiplatelet therapy option in patients undergoing coronary drug-eluting stents (DES) placement. Larger and more powerful randomized trials with precise sub-analyses are still necessary for further confirming these relevant benefits.

The Emperor's New Clothes: Dispelling the Myth of Improved Safety With Bare Metal

Article

Nov 2021

Tim Fischell

3- or 1-Month DAPT in Patients at High Bleeding Risk Undergoing Everolimus-Eluting Stent Implantation

Article

Sep 2021

Objectives The aim of this study was to evaluate 2 abbreviated dual-antiplatelet therapy (DAPT) regimens in patients at high bleeding risk (HBR) undergoing percutaneous coronary intervention (PCI). Background Current-generation drug-eluting stents are preferred over bare-metal stents for HBR patients, but their optimal DAPT management remains unknown. Methods The XIENCE Short DAPT program included 3 prospective, multicenter, single-arm studies enrolling HBR patients who underwent successful PCI with a cobalt-chromium everolimus-eluting stent. After 1 month (XIENCE 28 USA and XIENCE 28 Global) or 3 months (XIENCE 90) of DAPT, event-free patients discontinued the P2Y12 inhibitor. The postmarketing approval XIENCE V USA study was used as historical control in a propensity score–stratified analysis. Results A total of 3,652 patients were enrolled. The propensity-adjusted rate of the primary endpoint of all-cause mortality or myocardial infarction was 5.4% among 1,693 patients on 3-month DAPT versus 5.4% in the 12-month DAPT historical control (Pnoninferiority = 0.0063) and 3.5% among 1,392 patients on 1-month DAPT versus 4.3% in the 6-month DAPT historical control (Pnoninferiority = 0.0005). Bleeding Academic Research Consortium (BARC) types 2 to 5 bleeding was not significantly lower with 3- or 1-month DAPT, while BARC types 3 to 5 bleeding was reduced in both experimental groups. The rate of definite or probable stent thrombosis was 0.2% in XIENCE 90 (P < 0.0001 for the performance goal of 1.2%) and 0.3% in XIENCE 28. Conclusions Among HBR patients undergoing PCI with cobalt-chromium everolimus-eluting stents, DAPT for 1 or 3 months was noninferior to 6 or 12 months of DAPT for ischemic outcomes and may be associated with less major bleeding and a low incidence of stent thrombosis.

Acute thrombogenicity of fluoropolymer coated stents versus competitive drug-eluting stents under single antiplatelet therapy

Article

Jun 2021
INT J CARDIOL

Background: Recent clinical studies have suggested the feasibility of 1-month dual antiplatelet therapy (DAPT) for patients receiving drug-eluting stent (DES). Although our previous ex-vivo swine arteriovenous (AV) shunt studies under low dose heparin treatment suggested superior thromboresistance of fluoropolymer-coated everolimus-eluting stent (FP-EES) when compared to other polymer-based DESs, the relative thromboresistance of different DESs under single antiplatelet therapy (SAPT) has never been examined. This study aimed to evaluate platelet adhesion under SAPT in competitive DESs in the in vitro flow loop model and ex vivo swine AV shunt model. Methods: The thrombogenicity of FP-EES, BioLinx polymer zotarolimus-eluting stent (BL-ZES), and biodegradable polymer everolimus-eluting stent (BP-EES) was assessed acutely using the swine AV shunt model under aspirin or clopidogrel SAPT. Stents were immunostained using antibodies against platelets and inflammatory markers and evaluated by confocal microscopy. Also, the adhesion of platelet and albumin on the three DESs was assessed by an in-vitro flow loop model using human platelets under aspirin SAPT and fluorescent albumin, respectively. Results: In the shunt model, FP-EES showed significantly less platelet and inflammatory cell adhesion than BL-ZES and BP-EES. In the flow loop model, FP-EES showed significantly less platelet coverage and more albumin adsorption than BL-ZES and BP-EES. Conclusions: These results suggest FP-EES may have particular advantage for short-term DAPT compared to other DESs.

Biodegradable polymer drug-eluting stents versus durable polymer drug-eluting stents for percutaneous coronary intervention: a contemporary registry-based analysis

Article

May 2021
Coron Artery Dis

Aims: We aimed to compare the long-term outcomes of patients undergoing percutaneous coronary intervention (PCI) with biodegradable polymer drug-eluting stents (BP-DES) versus durable polymer drug-eluting stents (DP-DES). Methods and results: Among 11 517 PCIs with second-generation DES performed in our institution between 2007 and 2019, we identified 8042 procedures performed using DP-DES and 3475 using BP-DES. The primary outcome was target lesion failure, the composite target lesion revascularization (TLR), target vessel myocardial infarction and death. Propensity score matching was used to create a well-balanced cohort. Mean follow-up was 4.8 years. Of the 3413 matched pairs, 21% were females, and the mean age was 66 years. At 1 year, the primary outcome occurred in 8.3% patients versus 7.1% (P = 0.07), and TLR rate was 3% versus 2% (P = 0.006) in patients with DP-DES and BP-DES respectively. Within 5 years, the primary outcome occurred in 23.1% versus 23.4% (P = 0.44), and the rate of TLR was 7.2% versus 6.5% (P = 0.07) in patients with DP-DES and BP-DES, respectively. Conclusion: Similar rates of the composite outcome were observed throughout the entire follow-up. target vessel revascularization rates were lower in the DP-DES group at 1 year but equalized within 5 years.

Intracellular glutamine level determines vascular smooth muscle cell-derived thrombogenicity

Article

May 2021
Atherosclerosis

Background and aims The everolimus-eluting stent (EES), one of the effective stents for in-stent restenosis (ISR), has a lower incidence of stent thrombosis; however, the underlying mechanism remains unknown. This study aimed to identify the effects of everolimus on vascular metabolism and thrombogenicity and examine their mechanistic link. Methods EESs and bare-metal stents were implanted in rabbit iliac arteries with smooth muscle cell (SMC)-rich neointima induced by endothelial denudation. Four weeks after stent implantation, the stented arteries were examined for histological analysis and metabolomics. Additionally, everolimus effects in coronary artery SMCs metabolism, tissue factor (TF) expression, and procoagulant activity were assessed in vitro. Results EES-implanted arteries showed decreased neointima formation, less SMCs infiltration, and reduced TF expression. Concomitantly, they were metabolically characterized by increased levels of metabolites in amino acids, such as glutamine. Similarly, everolimus increased intracellular glutamine levels, decreased TF expression, and reduced procoagulant activity in SMCs in vitro. On the contrary, exogenous glutamine administration also increased intracellular glutamine level, decreased TF expression, and reduced procoagulant activity despite enhanced mammalian target of rapamycin (mTOR) activity. Conclusions Intracellular glutamine level is likely to determine vascular SMC-related thrombogenicity regardless of mTOR pathway activity. Therefore, increased intracellular glutamine level might contribute partially to the beneficial effect of EES use on stent thrombosis.

Differential impact of abluminal groove‐filled biodegradable‐polymer sirolimus‐eluting stent versus durable‐polymer everolimus‐eluting stent on and off dual antiplatelet therapy

Article

Jan 2021

Background Current guidelines recommend dual antiplatelet therapy (DAPT) following percutaneous coronary intervention for 6–12 months in patients with acute coronary syndrome (ACS) and 3–6 months in those with chronic coronary syndromes (CCS). Whether DAPT duration has a differential effect on outcomes following treatment of ischemic coronary disease with durable versus biodegradable drug‐eluting stent (DES) is poorly defined. Methods The TARGET All Comer study was a randomized trial of patients with ischemic coronary artery disease assigned to treatment with either a biodegradable polymer DES (Firehawk) or a durable polymer DES (XIENCE). This pre‐specified TARGET AC sub‐analysis sought to evaluate the 2‐year clinical outcomes before and after DAPT discontinuation. The primary endpoint was target lesion failure (TLF). Results A total of 1,296 (78.4%) of 1,653 randomized patients were included in this substudy, of which 1,210 (93.4%) remained on DAPT at 6 months, 863 (66.6%) at 12 months, and 409 (31.6%) at 2 years. There was no difference in TLF between patients treated with Firehawk and XIENCE stents from index procedure to DAPT discontinuation (8.0 and 7.7%, p > .99) or after DAPT discontinuation (2.9 vs. 3.8%, p = .16). After DAPT discontinuation, target vessel myocardial infarction (1.3 vs. 3.3%, p = .07), and ischemia‐driven target lesion revascularization (0.5 vs. 1.9%, p = .06) favored treatment with Firehawk. Conclusions Although TLF was comparable for both Firehawk and XIENCE stent groups before and after DAPT discontinuation, after DAPT discontinuation, there was a trend for less target vessel myocardial infarction and ischemia‐driven revascularization with the biodegradable polymer DES.

First-in-Man Evaluation of a Sirolimus-Eluting Stent With Abluminal Fluoropolymeric/Triflusal Coating With Ultrathin Struts by OCT at 9 Months' Follow-Up: The PROMETHEUS Study

Article

Dec 2020

Objectives We sought to investigate stent healing and neointimal hyperplasia with ihtDEStiny drug-eluting stent (DES) by optical coherence tomography (OCT) examination conducted 9 months after implantation. Background The currently used DES present certain features that have been linked separately to their better performance in terms of efficacy and safety. Methods First-in-man, prospective and multicenter study including patients treated with ihtDEStiny stent undergoing OCT examination at 9 months follow up. The ihtDEStiny stent is a sirolimus eluting stent with an oval shape ultrathin struts (68 μm) and an abluminal coating of a fluoropolymer containing the antiplatelet agent triflusal. Primary endpoint was the percentage of obstruction of the in-stent volume by the neointima. Results In 58 patients (63 lesions) in-stent late lumen loss was 0.11 ± 0.23 mm (95% CI 0.05–0.16) with only in 6% of stents being > 0.5 mm and in-segment binary stenosis was 1.6%. In OCT mean neointima volume obstruction was 10.5 ± 6.9% with a mean neointima thickness of 110.9 ± 89.8 μm. The proportion of uncovered struts was 2.5%, malapposed struts 1.1% and malapposed/uncovered struts 0.7% and no subclinical thrombi detected. Mean incomplete stent apposition area was 0.1 ± 0.1 mm². At 12 months target lesion revascularization rate was 3% and no stent thrombosis was reported. Conclusions In this study the ihtDEStiny stent has shown a very low degree of neointimal proliferation associated with a low rate of uncovered/malapposed struts and total absence of subclinical thrombi at 9 months follow up.

REabsorbable vs. DUrable Polymer Drug-Eluting Stents in All-Comer PatiEnts: the REDUCE registry

Article

Nov 2020
Coron Artery Dis

Background: While the superiority of reabsorbable-polymer drug-eluting stents (RP-DES) over bare-metal stents and first-generation durable-polymer (DP)-DES has been largely established, their advantage compared with new-generation DP-DES is still controversial. This study aimed was to compare clinical outcomes of all-comer patients undergoing percutaneous coronary intervention (PCI) with new generation DP-DES or RP-DES implantation. Methods: We prospectively enrolled 679 consecutive patients treated with PCI with RP-DES or DP-DES. The primary endpoint was the 1-year incidence of major adverse clinical events (MACE), a composite of death, myocardial infarction (MI), and target vessel revascularization (TVR). Target lesion revascularization (TLR) and definite stent thrombosis were also recorded. Results: A total of 439 (64.6%) received RP-DES and 240 (36.4%) received DP-DES. No significant difference in the incidence of MACE (5.9 vs. 4.9%; hazard ratio, 1.23; 95% confidence interval (CI), 0.61-2.49; P = 0.569), death (1.8 vs. 1.7%; hazard ratio, 1.09; 95% CI, 0.33-3.64; P = 0.882), MI (2.3 vs. 2.1%; hazard ratio, 1.05; 95% CI, 0.36-3.08; P = 0.927), TVR (2.3 vs. 1.3%; hazard ratio, 1.70; 95% CI, 0.47-6.20; P = 0.418), TLR (1.4 vs. 0.4%; hazard ratio, 3.06; 95% CI, 0.37-25.40; P = 0.301), and definite stent thrombosis (0.5 vs. 0.4%; hazard ratio, 1.09; 95% CI, 0.10-12.10; P = 0.942) was observed between RP-DES and DP-DES patients at 1-year follow-up. These results were confirmed in a propensity score-matched cohort (n = 134 per group). Conclusion: In our registry including a real-world population of all-comer patients undergoing PCI, RP-DES, or durable polymer-DES showed similar efficacy and safety at a 1-year follow-up.

Durable Polymer Versus Biodegradable Polymer Drug-Eluting Stents after Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome: The HOST-REDUCE-POLYTECH-ACS Trial

Article

Nov 2020

Background: Large scale randomized comparison of drug-eluting stents (DES) based on durable polymer (DP) versus biodegradable polymer (BP) technology is currently insufficient in patients with acute coronary syndrome (ACS). The present study sought to prove the non-inferiority of the DP-DES compared with the BP-DES in such patients. Methods: The HOST-REDUCE-POLYTECH-ACS trial is an investigator-initiated, randomized, open-label, adjudicator-blinded, multicenter, non-inferiority trial which compared the efficacy and safety of DP-DES and BP-DES in patients with ACS. The primary endpoint was patient oriented composite outcome (POCO, a composite of all-cause death, non-fatal myocardial infarction (MI), and any repeat revascularization) at 12 months. The key secondary endpoint was device oriented composite outcome (DOCO; a composite of cardiac death, target-vessel MI, or target lesion revascularization) at 12 months. Results: A total of 3413 patients were randomized to receive the DP-DES (1713 patients) and BP-DES (1700 patients). At 12 months, POCO occurred in 5.2% in the DP-DES group and 6.4% in the BP-DES group (Absolute risk difference: -1.2%, P non-inferiority <0.001). The key secondary endpoint, DOCO, occurred less frequently in the DP-DES group (DP-DES vs. BP-DES: 2.6% vs. 3.9%, HR 0.67, 95% CI 0.46-0.98, p=0.038), mostly due to a reduction in target lesion revascularization. The rate of spontaneous non-fatal MI and stent thrombosis were extremely low, with no significant difference between the 2 groups (0.6% vs. 0.8%; p=0.513 and 0.1% vs 0.4%; p=0.174, respectively). Conclusions: In ACS patients receiving percutaneous coronary intervention (PCI), DP-DES was non-inferior to BP-DES with regard to POCO at 12 months after index PCI. Clinical Trial Registration: URL: clinicaltrials.gov Unique identifier: NCT02193971

Design and rationale of the XIENCE short DAPT clinical program: An assessment of the safety of 3-month and 1-month DAPT in patients at high bleeding risk undergoing PCI with an everolimus-eluting stent

Article

Oct 2020

Background Dual antiplatelet therapy (DAPT) is key for the prevention of recurrent ischemic events after percutaneous coronary intervention (PCI); however, it increases the risk of bleeding complications. While new generation drug-eluting stents have been shown superior to bare-metal stents after a short DAPT course, the optimal DAPT duration in patients at high bleeding risk (HBR) remains to be determined. Trial design The XIENCE Short DAPT program consists of three prospective, single-arm studies (XIENCE 90, XIENCE 28 Global and XIENCE 28 USA) investigating 3- or 1-month DAPT durations in HBR patients undergoing PCI with the XIENCE stent. The XIENCE 90 study is being conducted in the US and enrolled 2047 subjects who discontinued DAPT at 3 months if they were free from myocardial infarction (MI), repeat coronary revascularization, stroke, or stent thrombosis. The XIENCE 28 program includes the USA study, enrolling 642 patients in US and Canada, and the Global study, enrolling 963 patients in Europe and Asia. In XIENCE 28, patients were to discontinue DAPT at 1 month post-PCI if event-free. The primary hypothesis for both XIENCE 90 and XIENCE 28 is that a short DAPT regimen will be non-inferior to a conventional DAPT duration with respect to the composite of all-cause death or MI. Patients enrolled in the prospective multicenter post-market XIENCE V USA study will be used as historical control group in a stratified propensity-adjusted analysis. Conclusions The XIENCE Short DAPT Program will provide insights into the safety and efficacy of 2 abbreviated DAPT regimens of 3- and 1-month duration in a large cohort of HBR patients undergoing PCI with the XIENCE stent.

Emerging therapies in coronary balloon angioplasty, stenting, and bioabsorbable scaffolds

Chapter

Jan 2020

Mortality from coronary artery disease, the leading cause of death globally, has been on the decline. Percutaneous coronary intervention, performed for over 40 years, has been a major contributor to this favorable trend, together with advances in surgical revascularization, adjunctive pharmacotherapy and risk factor modification. In this chapter, we provide an overview of percutaneous coronary interventions, focusing on the iterative development of devices that have facilitated treatment of increasingly complex coronary lesions, lower complication rates and increase procedural success. We review emerging technologies in percutaneous coronary interventions with their specific applications and advantages, including specialty angioplasty balloons for modifying calcific and fibrotic lesions, novel drug-eluting stents with improves safety profile, deliverability and designs to treat bifurcations, bioresorbable scaffolds that hold the promise of restoring vessel architecture as well as robotic percutaneous coronary intervention to tackle operator radiation exposure and orthopedic injuries related to wearing protective aprons, and the emerging use of 3D printing.

Single and multi-functional coating strategies for enhancing the biocompatibility and tissue integration of blood-contacting medical implants

Article

Aug 2020
BIOMATERIALS

Device-associated clot formation and poor tissue integration are ongoing problems with permanent and temporary implantable medical devices. These complications lead to increased rates of mortality and morbidity and impose a burden on healthcare systems. In this review, we outline the current approaches for developing single and multi-functional surface coating techniques that aim to circumvent the limitations associated with existing blood-contacting medical devices. We focus on surface coatings that possess dual hemocompatibility and biofunctionality features and discuss their advantages and shortcomings to providing a biocompatible and biodynamic interface between the medical implant and blood. Lastly, we outline the newly developed surface modifications techniques that use lubricant-infused coatings and discuss their unique potential and limitations in mitigating medical device-associated complications.

One‐year outcomes of patients undergoing complex percutaneous coronary intervention with three contemporary drug‐eluting stents

Article

Jun 2020

Objectives We aimed to evaluate the 1‐year outcomes of three everolimus‐eluting stents (EES) for complex percutaneous coronary intervention (PCI). Background It is controversial whether contemporary bioresorbable‐polymer drug‐eluting stents (BP‐DES) are associated with better outcomes compared with durable‐polymer DES (DP‐DES). Methods Patients undergoing PCI with cobalt‐chromium (CoCr)‐DP‐EES (Xience), platinum‐chromium (PtCr)‐DP‐EES (Promus), or PtCr‐BP‐EES (Synergy) at one high‐volume institution between 2015 and 2017 were included. The primary endpoint was 1‐year major adverse cardiac events (MACE), a composite of death, myocardial infarction, and target‐vessel revascularization. Associations were also examined in patients undergoing complex PCI. Multivariable analysis was conducted to adjust for baseline differences across groups. Results We included n = 5,446 patients (CoCr‐DP‐EES, n = 3,177; PtCr‐DP‐EES, n = 1,555; PtCr‐BP‐EES, n = 714). Patients treated with PtCr‐BP‐EES had higher comorbidity burden and procedural complexity. At 1 year, MACE rates were 8.9% for CoCr‐DP‐EES versus 8.9% for PtCr‐DP‐EES versus 8.6% for PtCr‐BP‐EES (p = .97). The incidence of definite/probable stent thrombosis (ST) was also similar (0.6 vs. 0.4 vs. 0.3%, p = .69). Complex PCI was performed in n = 2,894/5,446 (53.1%). At 1 year, MACE rates were 11.5 versus 10.7 versus 10.3%, respectively (p = .83). The incidence of definite/probable ST was also similar (0.9 vs. 0.3 vs. 0.3%, p = .22). On multivariable analysis, stent type was not an independent predictor of MACE either in the overall or in the complex PCI population. Conclusions We observed comparable 1‐year rates of MACE and definite/probable ST in patients undergoing PCI with CoCr‐DP‐EES, PtCr‐DP‐EES, and PtCr‐BP‐EES. Results were unchanged among patients undergoing complex PCI. Future multicenter randomized studies should confirm and extend our findings.

Fluorinated Biomaterials

Chapter

Jan 2020

David W Grainger

Naturally occurring organofluorine compounds are exceedingly rare; fluorinated materials are also seldom encountered naturally. Fluorine in the human body is only biochemically accumulated to any significance in skeletal and dental tissues. Nonetheless, human-produced fluorinated materials, primarily polymers, are extensively used in human implants, exhibiting a broad range of properties attractive for biomaterials applications. Synthetic organofluorine bonds impart interesting materials physical chemistry with associated new beneficial properties. Fluorinated polymers are generally recognized for outstanding chemical resistance, thermal stability, unique tribology, oxygen permeation, piezo-, pyro-, and ferro- electric and dielectric properties, and some fabrication features in small dimensions. Their notable biological responses to physiological fluids and tissues are diverse. Collectively, these properties are frequently exploited for biomaterials use both inside and outside the body. This chapter explores the unique structure-property relationships for fluorinated and perfluorinated biomaterials commonly found in a diverse array of clinical implants intended to improve human quality of life. Many observed biological properties of fluorinated materials beneficial to implants are, based on evidence to date, difficult to explain from fundamental principles. Soft tissue, vascular, ocular and biotechnology applications are common, while hard tissue and mechanical applications have frequently failed.

Comparison of Acute Thrombogenicity and Albumin Adsorption in Three Different Durable Polymer Coronary Drug-Eluting Stents

Article

Mar 2020

Aims: This study sought to compare thromboresistance and albumin binding capacity of different durable polymer DESs using dedicated preclinical and in vitro models. Methods and results: In an ex vivo swine arterio-venous shunt model, fluoropolymer everolimus-eluting stent (FP-EES) (n=14) was compared with two durable polymer DES (BioLinx polymer coated zotarolimus-eluting stent (BL-ZES)(n=9) and a CarboSil® elastomer polymer coated ridaforolimus-eluting stent (EP-RES)(n=6)), and bare metal stents (BMS)(n=10). Stents underwent immunostaining using a cocktail of anti-platelet antibodies and a marker for inflammation and then were evaluated by confocal microscopy (CM). Albumin retention was assessed by using a flow loop model with labeled human serum albumin [FP-EES(n=8), BL-ZES(n=4), EP-RES(n=4), and BMS(n=7)] and scanned by CM. The area of platelet adherence (normalized to total stent surface area) was lower in order of FP-EES (9.8%), BL-ZES (32.7%), EP-RES (87.6%) and BMS (202.0%) and inflammatory cell densities was least for FP-EES<BL-ZES<EP-RES<BMS. Although nearly full coverage by albumin binding was shown for all durable polymer DES, FP-EES showed significantly greater intensity of albumin as compared to BL-ZES, EP-RES and BMS (FP-EES;79.0%, BL-ZES;13.2%, EP-RES;6.1%, BMS;1.5%). Conclusions: These results suggest that thromboresistance, and albumin retention vary by polymer type and that these differences might result in different suitability for short-term dual antiplatelet therapy.

Vapor-Deposited Nanocoatings for Sustained Zero-Order Release of Antiproliferative Drugs

Article

Feb 2020

Drug-eluting stents have been widely used in the treatment of coronary heart diseases, but the long-term efficacy has been dependent on the control of drug release kinetics. Though evenly distributed release with minimal burst release is much desired for the antiproliferative drugs used on stents, strategies for sustained zero-order release have not been specifically identified. We investigated vapor-based fabrication of polymer nanocoatings for the encapsulation of antiproliferative drugs. Drug release kinetics was regulated by adjusting the composition and thickness of the nanocoatings. Zero-order release of atorvastatin and sirolimus for 30 days was achieved using a poly(2-dimethylamino ethyl methacrylate-co-ethylene glycol diacrylate) (PDE) nanocoating with a monomer/cross-linker molar ratio of 0.78. The drug release rate was modulated using drug dose and coating thickness. The combination of coating surface and drug release suppressed the viability and proliferation of human coronary artery smooth muscle cells to below 57% at dose density as low as 10 μg/cm2. The PDE nanocoatings also reduced surface platelet adhesion without detrimental effect on red blood cells. The findings of this study demonstrate the potential of applying vapor-deposited polymer nanocoatings in modulating the release kinetics and thus improving the therapeutic efficacy of drug-eluting stents.

Comparison of clinical outcomes between Magmaris and Orsiro drug eluting stent at 12 months: Pooled patient level analysis from BIOSOLVE II–III and BIOFLOW II trials

Article

Full-text available

Nov 2019
INT J CARDIOL

Background: The aim of this study was to compare the 12-month clinical outcomes of patients treated with Magmaris or Orsiro. Second generation drug-eluting absorbable metal scaffold Magmaris (Dreams 2G) has proved to be safe and effective in the BIOSOLVE-II study. Similarly, biodegradable polymer sirolimus-eluting stent, Orsiro has shown notable clinical results even in all-comer populations. Methods: Magmaris group patients were taken from the BIOSOLVE-II and BIOSOLVE-III trials, while the patients from Orsiro group were enrolled in BIOFLOW-II trial. The primary outcome was explored using a time-to-event assessment of the unadjusted clinical outcomes for target lesion failure (TLF) at 12 months, followed by a multivariate analysis adjusting for all the significantly different covariates between the groups. Results: The study population consisted of 482 patients (521 lesions), 184 patients (189 lesions) in Magmaris group and 298 patients (332 lesions) in Orsiro group. The mean age was 65.5 ± 10.8 and 62.7 ± 10.4 years in Magmaris and Orsiro groups, respectively (p = 0.005). Magmaris and Orsiro unadjusted TLF rates were 6.0 and 6.4% with no significant difference between the groups (p = 0.869). In the multivariate analysis, there were no meaningful differences between Magmaris and Orsiro groups. Finally, none of the groups presented device thrombosis cases at 12 months. Conclusion: At 12 months there were no significant differences between Magmaris and Orsiro groups neither in the unadjusted assessment nor in the multivariate analysis for target lesion failure. These results should be taken as hypothesis generating and may warrant a head to head comparison on a randomized fashion.

Imaging Human Platelet Adhesion and Albumin Retention to Coronary Stents in Real Time

Article

Sep 2019

Everolimus-Eluting Biodegradable Polymer Versus Everolimus-Eluting Durable Polymer Stent for Coronary Revascularization in Routine Clinical Practice

Article

Full-text available

Aug 2019

Objectives: The aim of this study was to compare the efficacy and safety of a thin-strut, biodegradable-polymer everolimus-eluting stent (BP-EES) (Synergy, Boston Scientific, Marlborough, Massachusetts) and a thin-strut, durable-polymer everolimus-eluting stent (DP-EES) (XIENCE, Abbott Vascular, Abbott Park, Illinois) in an all-comers population. Background: BP-EES have been shown to be noninferior to DP-EES in randomized trials in patients at low to moderate risk. Methods: Among 7,042 consecutive patients who underwent percutaneous coronary intervention between December 2012 and December 2016, 3,870 patients were exclusively treated with BP-EES (n = 1,343) or with DP-EES (n = 2,527). After propensity score matching, the final study population consisted of 1,041 matched patients. The primary endpoint was the device-oriented composite endpoint (cardiac death, target vessel myocardial infarction, and target lesion revascularization) at 12 months. Results: The device-oriented composite endpoint did not differ between the 2 groups (7.8% with BP-EES vs. 7.1% with DP-EES; hazard ratio: 1.12; 95% confidence interval: 0.81 to 1.53; p = 0.49). There were no differences in rates of cardiac death (3.0% vs. 3.0%; p = 1.00), target vessel myocardial infarction (3.6% vs. 3.1%; p = 0.53), and target lesion revascularization (3.0% vs. 2.5%; p = 0.41). The rate of acute stent thrombosis was significantly higher in the BP-EES group compared with the DP-EES group (1.2% vs. 0.3%; hazard ratio: 4.00; 95% confidence interval: 1.13 to 14.19; p = 0.032). At 12 months, the frequency of definite stent thrombosis did not differ (1.5% vs. 0.9%; hazard ratio: 1.67; 95% confidence interval: 0.73 to 3.82; p = 0.22). Conclusions: In this consecutively enrolled percutaneous coronary intervention population reflecting routine clinical practice, no difference in the device-oriented composite endpoint between BP-EES and DP-EES was observed throughout 12 months. There was a higher rate of acute stent thrombosis with the BP-EES, a difference that disappeared at 1 year. (CARDIOBASE Bern PCI Registry; NCT02241291).

Acute Thrombogenicity of SYNERGY Drug-Eluting Stent

Article

Aug 2019

Sripal Bangalore

Long-Term Effect of Ultrathin-Strut Versus Thin-Strut Drug-Eluting Stents in Patients With Small Vessel Coronary Artery Disease Undergoing Percutaneous Coronary Intervention: A Subgroup Analysis of the BIOSCIENCE Randomized Trial

Article

Full-text available

Aug 2019

Background: Randomized trials evaluating the Orsiro biodegradable polymer sirolimus-eluting stent (BP-SES; 60 and 80 μm strut thickness for stent diameters ≤3 and >3 mm, respectively) did not stratify according to vessel size and failed to specify the impact of ultrathin-strut thickness on long-term clinical outcomes compared with durable polymer everolimus-eluting stents (DP-EES). We sought to assess the long-term effect of ultrathin-strut (60 μm) BP-SES versus thin-strut (81 μm) DP-EES on long-term outcomes in patients undergoing percutaneous coronary revascularization for small vessel disease. Methods: In a subgroup analysis of the randomized, multicenter, noninferiority BIOSCIENCE trial, patients with stable coronary artery disease or acute coronary syndrome randomly assigned to treatment with BP-SES or DP-EES were stratified according to vessel size (≤3 mm versus >3 mm) as a surrogate to compare patients treated with ultrathin-strut versus thin-strut drug-eluting stent. The primary end point was target lesion failure, a composite of cardiac death, target vessel myocardial infarction, and clinically indicated target lesion revascularization, within 5 years. Results: Among 2109 patients, 1234 (59%) were treated for small vessel disease. At 5 years, target lesion failure occurred in 124 patients (cumulative incidence, 22.3%) treated with ultrathin-strut BP-SES and 109 patients (18.3%) treated with thin-strut DP-EES (rate ratio, 1.22; 95% CI, 0.94-1.58; P=0.13). Cumulative incidences of cardiac death, target vessel myocardial infarction, and clinically indicated target lesion revascularization and definite stent thrombosis at 5 years were similar in patients treated with ultrathin-strut BP-SES and thin-strut DP-EES. After adjustment for potential confounders, there was no significant interaction between vessel size and treatment effect of BP-SES versus DP-EES. Conclusions: We found no significant difference in clinical outcomes throughout 5 years between patients with small vessel disease treated with ultrathin-strut BP-SES versus thin-strut DP-EES. Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01443104.

Drug-eluting coronary stents: insights from preclinical and pathology studies

Article

Jul 2019

Implantation of drug-eluting stents (DES) is the dominant treatment strategy for patients with symptomatic coronary artery disease. However, the first-generation DES had substantial drawbacks, including delayed healing, local hypersensitivity reactions and neoatherosclerosis, which all led to a steady increase in major adverse cardiovascular events over time. Subsequently, newer-generation DES were introduced with thinner struts, different scaffold designs (to improve deliverability while maintaining radial strength), different durable and biodegradable polymers - and in some cases no polymer (to improve vascular biocompatibility) - and new antiproliferative drug types and doses. Currently, >30 different DES are commercially available in Europe, with fewer available in the USA but with many new entrants coming onto the US market in the next few years. Never before have cardiologists been faced with so many choices of stent, each with its own unique design. In this Review, we detail preclinical and pathology studies for each stent design, examining thromboresistance, speed of neointimal coverage and completeness of healing, including endothelialization. We conclude by discussing how these design characteristics might affect the potential for shortening the minimum duration of dual antiplatelet therapy needed after coronary intervention.

Biodegradable polymer biolimus-eluting stent (NOBORI®) for the treatment of coronary artery lesions: Review of concept and clinical results

Article

Full-text available

Feb 2014

First-generation drug-eluting stents have raised concerns regarding the risk of late and very late stent thrombosis compared with bare metal stents and require prolonged dual antiplatelet therapy. Despite extensive investigations, the physiopathology of these late events remains incompletely understood. Aside from patient- and lesion-related risk factors, stent polymer has been cited as one of the potential causes. In fact, the persistence of durable polymer after complete drug release has been shown to be responsible for local hypersensitivity and inflammatory reactions. Third-generation drug-eluting stents with more biocompatible or biodegradable polymers have subsequently been developed to address this problem. In this article, we evaluate and discuss the concept and clinical results (safety and efficacy) of a third-generation drug-eluting stent with biodegradable polymer: the Nobori® stent.

Cathepsin G-Dependent Modulation of Platelet Thrombus Formation In Vivo by Blood Neutrophils

Article

Full-text available

Aug 2013
PLOS ONE

Neutrophils are consistently associated with arterial thrombotic morbidity in human clinical studies but the causal basis for this association is unclear. We tested the hypothesis that neutrophils modulate platelet activation and thrombus formation in vivo in a cathepsin G-dependent manner. Neutrophils enhanced aggregation of human platelets in vitro in dose-dependent fashion and this effect was diminished by pharmacologic inhibition of cathepsin G activity and knockdown of cathepsin G expression. Tail bleeding time in the mouse was prolonged by a cathepsin G inhibitor and in cathepsin G knockout mice, and formation of neutrophil-platelet conjugates in blood that was shed from transected tails was reduced in the absence of cathepsin G. Bleeding time was highly correlated with blood neutrophil count in wildtype but not cathepsin G deficient mice. In the presence of elevated blood neutrophil counts, the anti-thrombotic effect of cathepsin G inhibition was greater than that of aspirin and additive to it when administered in combination. Both pharmacologic inhibition of cathepsin G and its congenital absence prolonged the time for platelet thrombus to form in ferric chloride-injured mouse mesenteric arterioles. In a vaso-occlusive model of ischemic stroke, inhibition of cathepsin G and its congenital absence improved cerebral blood flow, reduced histologic brain injury, and improved neurobehavioral outcome. These experiments demonstrate that neutrophil cathepsin G is a physiologic modulator of platelet thrombus formation in vivo and has potential as a target for novel anti-thrombotic therapies.

Polymer coatings on drug-eluting stents: Samson's hair and Achilles' heel?

Article

Full-text available

Jul 2013

Biodegradable Polymer Biolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent

Article

Full-text available

May 2013

Objectives: NEXT (NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial) was designed for evaluating the noninferiority of a biolimus-eluting stent (BES) relative to an everolimus-eluting stent (EES) in terms of target lesion revascularization (TLR) at 1 year. Background: Efficacy and safety data comparing biodegradable polymer BES with durable polymer cobalt-chromium EES are currently limited. Methods: The NEXT trial is a prospective, multicenter, randomized, open-label, noninferiority trial comparing BES with EES. Between May and October 2011, 3,235 patients were randomly assigned to receive either BES (n = 1,617) or EES (n = 1,618). Results: At 1 year, the primary efficacy endpoint of TLR occurred in 67 patients (4.2%) in the BES group, and in 66 patients (4.2%) in the EES group, demonstrating noninferiority of BES relative to EES (p for noninferiority <0.0001, and p for superiority = 0.93). Cumulative incidence of definite stent thrombosis was low and similar between the 2 groups (0.25% vs. 0.06%, p = 0.18). An angiographic substudy enrolling 528 patients (BES: n = 263, and EES: n = 265) demonstrated noninferiority of BES relative to EES regarding the primary angiographic endpoint of in-segment late loss (0.03 ± 0.39 mm vs. 0.06 ± 0.45 mm, p for noninferiority <0.0001, and p for superiority = 0.52) at 266 ± 43 days after stent implantation. Conclusions: One-year clinical and angiographic outcome after BES implantation was noninferior to and not different from that after EES implantation in a mostly stable coronary artery disease population. One-year clinical outcome after both BES and EES use was excellent, with a low rate of TLR and extremely low rate of stent thrombosis.

Biological responses in stented arteries

Article

Full-text available

May 2013
CARDIOVASC RES

Vascular walls change their dimension and mechanical properties in response to injury such as balloon angioplasty and endovascular stent implantation. Placement of bare metal stents induces neointimal proliferation/restenosis which progresses through different phases of repair with time involving a cascade of cellular reactions. These phases just like wound healing comprise distinct steps consisting of thrombosis, inflammation, proliferation and migration followed by remodeling. It is noteworthy that animals show a rapid progression of healing after stent deployment compared with man. During stenting, endothelial cells are partially to completely destroyed or crushed along with medial wall injury and stretching promoting activation of platelets, and thrombus formation accompanied by inflammatory reaction. Macrophages and platelets play a central role through the release of cytokines and growth factors that induce vascular smooth muscle cell accumulation within the intima. Smooth muscle cells undergo complex phenotypic changes including migration and proliferation from the media towards the intima, transition from a contractile to a synthetic phenotype and the molecular mechanism responsible for this change are highlighted in this review. Since studies in animals and man show that smooth muscle cells play a dominant role in restenosis, drugs like rapamycin and paclitaxel have been coated on stent with polymers to allow local slow release of drugs, which have resulted in dramatic reduction of restenosis that was once the Achilles heal of interventional cardiologists.

S6K1 and mTOR regulate Rac1-driven platelet activation and aggregation

Article

Full-text available

Jul 2011
BLOOD

Platelet activation and thrombus formation are under the control of signaling systems that integrate cellular homeostasis with cytoskeletal dynamics. Here, we identify a role for the ribosome protein S6 kinase (S6K1) and its upstream regulator mTOR in the control of platelet activation and aggregate formation under shear flow. Platelet engagement of fibrinogen initiated a signaling cascade that triggered the activation of S6K1 and Rac1. Fibrinogen-induced S6K1 activation was abolished by inhibitors of Src kinases, but not Rac1 inhibitors, demonstrating that S6K1 acts upstream of Rac1. S6K1 and Rac1 interacted in a protein complex with the Rac1 GEF TIAM1 and colocalized with actin at the platelet lamellipodial edge, suggesting that S6K1 and Rac1 work together to drive platelet spreading. Pharmacologic inhibitors of mTOR and S6K1 blocked Rac1 activation and prevented platelet spreading on fibrinogen, but had no effect on Src or FAK kinase activation. mTOR inhibitors dramatically reduced collagen-induced platelet aggregation and promoted the destabilization of platelet aggregates formed under shear flow conditions. Together, these results reveal novel roles for S6K1 and mTOR in the regulation of Rac1 activity and provide insights into the relationship between the pharmacology of the mTOR system and the molecular mechanisms of platelet activation.

Final 5-Year Follow-Up of a Randomized Controlled Trial of Everolimus- and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice: The COMPARE Trial.

Article

Full-text available

Jun 2011

This study sought to report the 5-year outcomes of everolimus-eluting stents (EES) and paclitaxel-eluting stents (PES) in an all-comers population undergoing percutaneous coronary intervention (PCI). The medium-term 1 and 2-year results of the prospective randomized COMPARE trial (A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice) showed superior clinical outcomes with EES compared with PES in an all-comers PCI population. Whether this benefit is sustained over longer-term follow-up is unknown. Furthermore, systematic long-term follow-up data on these metallic drug eluting stents with durable polymers are scarce. We randomly assigned 1,800 patients undergoing PCI to EES or PES. The pre-specified composite primary endpoint was death, myocardial infarction (MI), or target vessel revascularization (TVR). Follow-up at 5 years was completed in 1,791 (99.5%) patients. Treatment with EES compared with PES led to a relative risk reduction of the primary endpoint by 27% (18.4% vs. 25.1%, p = 0.0005), driven by lower rates of MI (7.0% vs. 11.5%, p = 0.001) and TVR (7.4% vs. 11.4%, p = 0.003), but not with mortality (9.0% vs. 10.3%, relative risk 0.88, p = 0.36). Moreover, patients treated with EES compared with PES had lower rates of definite/probable stent thrombosis at 5 years (3.1% vs. 5.9%, p = 0.005). The hazard curves for TVR, MI, and stent thrombosis diverge over the first 3 years and, subsequently, progress in parallel. The early- and medium-term superiority of EES over PES measured both by safety and efficacy endpoints is sustained at 5 years in this all-comer population. (A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice [COMPARE]; NCT01016041). Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Stent Thrombogenicity Early in High-Risk Interventional Settings Is Driven by Stent Design and Deployment and Protected by Polymer-Drug Coatings

Article

Full-text available

Mar 2011
CIRCULATION

Stent thrombosis is a lethal complication of endovascular intervention. Concern has been raised about the inherent risk associated with specific stent designs and drug-eluting coatings, yet clinical and animal support is equivocal. We examined whether drug-eluting coatings are inherently thrombogenic and if the response to these materials was determined to a greater degree by stent design and deployment with custom-built stents. Drug/polymer coatings uniformly reduce rather than increase thrombogenicity relative to matched bare metal counterparts (0.65-fold; P=0.011). Thick-strutted (162 μm) stents were 1.5-fold more thrombogenic than otherwise identical thin-strutted (81 μm) devices in ex vivo flow loops (P<0.001), commensurate with 1.6-fold greater thrombus coverage 3 days after implantation in porcine coronary arteries (P=0.004). When bare metal stents were deployed in malapposed or overlapping configurations, thrombogenicity increased compared with apposed, length-matched controls (1.58-fold, P=0.001; and 2.32-fold, P<0.001). The thrombogenicity of polymer-coated stents with thin struts was lowest in all configurations and remained insensitive to incomplete deployment. Computational modeling-based predictions of stent-induced flow derangements correlated with spatial distribution of formed clots. Contrary to popular perception, drug/polymer coatings do not inherently increase acute stent clotting; they reduce thrombosis. However, strut dimensions and positioning relative to the vessel wall are critical factors in modulating stent thrombogenicity. Optimal stent geometries and surfaces, as demonstrated with thin stent struts, help reduce the potential for thrombosis despite complex stent configurations and variability in deployment.

Blood-borne tissue factor: Another view of thrombosis

Article

Full-text available

Apr 1999

Arterial thrombosis is considered to arise from the interaction of tissue factor (TF) in the vascular wall with platelets and coagulation factors in circulating blood. According to this paradigm, coagulation is initiated after a vessel is damaged and blood is exposed to vessel-wall TF. We have examined thrombus formation on pig arterial media (which contains no stainable TF) and on collagen-coated glass slides (which are devoid of TF) exposed to flowing native human blood. In both systems the thrombi that formed during a 5-min perfusion stained intensely for TF, much of which was not associated with cells. Antibodies against TF caused approximately 70% reduction in the amount of thrombus formed on the pig arterial media and also reduced thrombi on the collagen-coated glass slides. TF deposited on the slides was active, as there was abundant fibrin in the thrombi. Factor VIIai, a potent inhibitor of TF, essentially abolished fibrin production and markedly reduced the mass of the thrombi. Immunoelectron microscopy revealed TF-positive membrane vesicles that we frequently observed in large clusters near the surface of platelets. TF, measured by factor Xa formation, was extracted from whole blood and plasma of healthy subjects. By using immunostaining, TF-containing neutrophils and monocytes were identified in peripheral blood; our data raise the possibility that leukocytes are the main source of blood TF. We suggest that blood-borne TF is inherently thrombogenic and may be involved in thrombus propagation at the site of vascular injury.

Stent and Artery Geometry Determine Intimal Thickening Independent of Arterial Injury

Article

Full-text available

Mar 2000
CIRCULATION

Clinical trials show that larger immediate postdeployment stent diameters provide greater ultimate luminal size, whereas animal data show that arterial injury and stent design determine late neointimal thickening. At deployment, a stent stretches a vessel, imposing a cross-sectional polygonal luminal shape that depends on the stent design, with each strut serving as a vertex. We asked whether this design-dependent postdeployment luminal geometry affects late neointimal thickening independently of the extent of strut-induced injury. Stainless steel stents of 3 different configurations were implanted in rabbit iliac arteries for 3 or 28 days. Stents designed with 12 struts per cross section had 50% to 60% less mural thrombus and 2-fold less neointimal area than identical stents with only 8 struts per cross section. Sequential histological sectioning of individual stents showed that immediate postdeployment luminal geometry and subsequent neointimal area varied along the course of each stent subunit. Mathematical modeling of the shape imposed by the stent on the artery predicted late neointimal area, based on the re-creation of a circular vessel lumen within the confines of the initial stent-imposed polygonal luminal shape. Immediate postdeployment luminal geometry, dictated by stent design, determines neointimal thickness independently of arterial injury and may be useful for predicting patterns of intimal growth for novel stent designs.

Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor

Article

Full-text available

Aug 2000

We describe thrombogenic tissue factor (TF) on leukocyte-derived microparticles and their incorporation into spontaneous human thrombi. Polymorphonuclear leukocytes and monocytes transfer TF(+) particles to platelets, thereby making them capable of triggering and propagating thrombosis. This phenomenon calls into question the original dogma that vessel wall injury and exposure of TF within the vasculature to blood is sufficient for the occurrence of arterial thrombosis. The transfer of TF(+) leukocyte-derived particles is dependent on the interaction of CD15 and TF with platelets. Both the inhibition of TF transfer to platelets by antagonizing the interaction CD15 with P-selectin and the direct interaction of TF itself suggest a novel therapeutic approach to prevent thrombosis.

Drug eluting stents: Are human and animal studies comparable?

Article

Full-text available

Mar 2003
HEART

Animal models of stenting probably predict human responses as the stages of healing are remarkably similar. What is characteristically different is the temporal response to healing, which is substantially prolonged in humans. The prevention of restenosis in recent clinical trials of drug eluting stents may represent a near absent or incomplete phase of intimal healing. Continued long term follow up of patients with drug eluting stents for major adverse cardiac events and angiographic restenosis is therefore imperative.

Findings of intravascular ultrasound during acute stent thrombosis

Article

Full-text available

Dec 2004
HEART

To evaluate the potential role of intravascular ultrasound (IVUS) in evaluating patients experiencing an episode of acute stent thrombosis. Prospective observational study in a cardiac catheterisation laboratory in a university teaching hospital. IVUS was used to examine 12 patients undergoing coronary interventions for stent thrombosis to gain further mechanistic insights and to guide treatment. IVUS studies were obtained before and after intervention with a motorised pullback device. Qualitative and volumetric IVUS analyses. Angiographically, 10 patients had occluded vessels and two patients had intraluminal filling defects within the stent. IVUS showed an occlusive thrombus in all patients. Thrombus volume was 90 (77) mm3, which was 51 (21)% of total stent volume. There was evidence of severe stent underexpansion in most patients and no patient fulfilled standard criteria for optimal stent implantation. Stent malapposition was detected in four patients, edge dissections were seen in two patients, and significant inflow-outflow disease was present in 11 patients. During interventions IVUS findings led to the use of higher pressures or larger balloons than those used during initial stenting in 10 patients. In addition, four patients required additional stenting, whereas a thrombectomy device alone was selected for one patient. After the procedure final minimum stent area (7.1 (2.1) v 5.3 (2) mm2, p < 0.005) and stent expansion (83.2 (17) v 62.1 (15)%, p < 0.005) improved compared with pre-interventional values. However, residual lining thrombus was still visualised in eight patients (25 (19) mm3, accounting for a 17% of final stent volume). IVUS provides an attractive technique to characterise fully the pattern of stent thrombosis, to identify readily the underlying mechanical predisposing factors, and to guide repeated coronary interventions.

mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets

Article

Full-text available

Apr 2007

New activities of human platelets continue to emerge. One unexpected response is new synthesis of proteins from previously transcribed RNAs in response to activating signals. We previously reported that activated human platelets synthesize B-cell lymphoma-3 (Bcl-3) under translational control by mammalian target of rapamycin (mTOR). Characterization of the ontogeny and distribution of the mTOR signaling pathway in CD34+ stem cell-derived megakaryocytes now demonstrates that they transfer this regulatory system to developing proplatelets. We also found that Bcl-3 is required for condensation of fibrin by activated platelets, demonstrating functional significance for mTOR-regulated synthesis of the protein. Inhibition of mTOR by rapamycin blocks clot retraction by human platelets. Platelets from wild-type mice synthesize Bcl-3 in response to activation, as do human platelets, and platelets from mice with targeted deletion of Bcl-3 have defective retraction of fibrin in platelet-fibrin clots mimicking treatment of human platelets with rapamycin. In contrast, overexpression of Bcl-3 in a surrogate cell line enhanced clot retraction. These studies identify new features of post-transcriptional gene regulation and signal-dependant protein synthesis in activated platelets that may contribute to thrombus and wound remodeling and suggest that posttranscriptional pathways are targets for molecular intervention in thrombotic disorders.

Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor

Article

Jul 2000

We describe thrombogenic tissue factor (TF) on leukocyte-derived microparticles and their incorporation into spontaneous human thrombi. Polymorphonuclear leukocytes and monocytes transfer TF+particles to platelets, thereby making them capable of triggering and propagating thrombosis. This phenomenon calls into question the original dogma that vessel wall injury and exposure of TF within the vasculature to blood is sufficient for the occurrence of arterial thrombosis. The transfer of TF+ leukocyte-derived particles is dependent on the interaction of CD15 and TF with platelets. Both the inhibition of TF transfer to platelets by antagonizing the interaction CD15 with P-selectin and the direct interaction of TF itself suggest a novel therapeutic approach to prevent thrombosis.

Drug eluting stents: are human and animal studies comparable?

Article

Feb 2003
Br Heart J

Renu Virmani

Causes of Early Stent Thrombosis in Patients Presenting With Acute Coronary Syndrome An Ex Vivo Human Autopsy Study

Article

Apr 2014

We interrogated our autopsy registry to investigate the histopathologic features of early stent thrombosis (ST) in patients presenting with acute coronary syndrome (ACS). The occurrence of early ST following percutaneous coronary intervention (PCI) for ACS remains a clinical problem despite advances in stent technology in both bare metal and drug-eluting stents. - Sixty-seven stented coronary lesions from 59 patients who presented with ACS and died within 30 days were included. Stented segments were cross-sectioned at 3-4 mm intervals, evaluated by light microscopy, and morphometric analysis was performed. Early ST (<30 days of PCI) was identified in 34 (58%) of the 59 patients. Early ST was dependent on the underlying plaque morphology and underlying thrombus burden: presence of necrotic core prolapse was more frequent in thrombosed lesions compared with patent lesions (70% vs. 43%, p=0.045) and maximum underlying thrombus thickness was significantly greater in thrombosed versus patent lesions. All 3 patients with false lumen stenting had ST. Detailed analysis revealed that the percentage of necrotic core prolapse, medial tear, or incomplete apposition was significantly greater in the early ST compared with patent group (28% vs.11%, p<0.001, 27% vs. 15% p=0.004, and 34% vs. 18% p =0.008, respectively). Multivariate analysis revealed that maximum depth of strut penetration, % strut with medial tear, and % struts with incomplete apposition were the primary indicators of early ST. - The current autopsy study highlights the impact of thrombus burden and suboptimal stent implantation in unstable lesions as a trigger of early ST, suggesting that improvement in implantation technique and refinement of stent design may improve clinical outcomes of ACS patients.

Impact of the Everolimus-Eluting Stent on Stent Thrombosis : A Meta-Analysis of 13 Randomized Trials

Article

Oct 2011

Objectives We evaluated the impact of the everolimus-eluting stent (EES) on the frequency of stent thrombosis (ST), target vessel revascularization (TVR), myocardial infarction (MI), and cardiac death in randomized controlled trials comparing the EES to non–everolimus-eluting drug-eluting stents (EE-DES). Background Whether or not the unique properties of the EES translate into reductions in ST remains unknown. Methods We searched MEDLINE, Scopus, the Cochrane Library, and Internet sources for articles comparing outcomes between EES and non–EE-DES without language or date restriction. Randomized controlled trials reporting the frequency of ST were included. Variables relating to patient and study characteristics and clinical endpoints were extracted. Results We identified 13 randomized trials (n = 17,101) with a weighted mean follow-up of 21.7 months. Compared with non–EE-DES, the EES significantly reduced ST (relative risk [RR]: 0.55; 95% confidence interval [CI]: 0.38 to 0.78; p = 0.001), TVR (RR: 0.77; 95% CI: 0.64 to 0.92; p = 0.004), and MI (RR: 0.78; 95% CI: 0.64 to 0.96; p = 0.02). There was no difference in cardiac mortality between the groups (RR: 0.92; 95% CI: 0.74 to 1.16; p = 0.38). The treatment effect was consistent by different follow-up times and duration of clopidogrel use. The treatment effects increased with higher baseline risks of the respective control groups with the strongest correlation observed for ST (R2 = 0.89, p < 0.001). Conclusions Intracoronary implantation of the EES is associated with highly significant reductions in ST with concordant reductions in TVR and MI compared to non–EE-DES. Whether these effects apply to different patient subgroups and DES types merits further investigation.

A Multiple Comparison Procedure for Comparing Several Treatments with a Control

Article

Dec 1955

CHARLES W. DUNNETT

The abstract for this document is available on CSA Illumina.To view the Abstract, click the Abstract button above the document title.

Abluminal biodegradable polymer biolimus-eluting stent versus durable polymer everolimus-eluting stent (COMPARE II): A randomised, controlled, non-inferiority trial

Article

Jan 2013
LANCET

Background: Drug-eluting stents with durable biocompatible or biodegradable polymers have been developed to address the risk of thrombosis associated with first-generation drug-eluting stents. We aimed to compare the safety and efficacy of a biodegradable polymer-coated biolimus-eluting stent with a thin-strut everolimus-eluting stent coated with a durable biocompatible polymer. Methods: This open-label, prospective, randomised, controlled, non-inferiority trial was undertaken at 12 sites across Europe. We used limited exclusion criteria (age >18 years, life expectancy >5 years, reference vessel diameter 2·0-4·0 mm) to enrol patients eligible for percutaneous coronary intervention. Patients were randomly allocated (2:1) by computer-generated random numbers to receive either a biodegradable polymer biolimus-eluting stent (Nobori, Terumo, Tokyo, Japan) or a durable fluoropolymer-based everolimus-eluting stent (Xience V or Prime, Abbott Vascular, Santa Clara, CA, USA, or Promus, Boston Scientific, Natick, MA, USA). The primary endpoint was a composite of safety (cardiac death and non-fatal myocardial infarction) and efficacy (clinically indicated target vessel revascularisation) at 12 months, analysed by intention to treat. Patients received dual antiplatelet therapy for 12 months after discharge. The trial is registered with ClinicalTrials.gov, number NCT01233453. Findings: From Jan 12, 2009, to Feb 7, 2011, we enrolled 2707 patients (4025 lesions), 1795 of whom were assigned to receive the biolimus-eluting stent (2638 lesions) and 912 to an everolimus-eluting stent (1387 lesions). 2688 (99·3%) patients completed 12 months' follow-up. Significantly more patients in the biolimus-eluting stent group received a non-assigned stent than did those in the everolimus-eluting stent group (105 [5·9%] vs 19 [2·1%]; p<0·0001). The primary endpoint occurred in 93 (5·2%) patients in the biolimus-eluting stent group and 44 (4·8%) patients in the everolimus-eluting stent group at 12 months (relative risk 1·07 [95% CI 0·75-1·52]; p(non-inferiority)<0·0001). Analysis per protocol did not change the outcome of this trial (p(non-inferiority)<0·0001). Interpretation: Biodegradable polymer biolimus-eluting stents are as safe and efficacious as the current standard of a thin-strut everolimus-eluting stent with a durable biocompatible polymer. We need to follow-up patients for longer to show whether the biolimus-eluting stent reduces the risk of stent thrombosis after 1 year when compared with the everolimus-eluting stent. Funding: Terumo Europe (Leuven, Belgium) and the Research Foundation of the Cardiology Department, Maasstad Hospital (Rotterdam, Netherlands).

Development and Validation of a Stent Thrombosis Risk Score in Patients With Acute Coronary Syndromes

Article

Nov 2012

This study sought to develop a practical risk score to predict the risk of stent thrombosis (ST) after percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS). ST is a rare, yet feared complication after PCI with stent implantation. A risk score for ST after PCI in ACS can be a helpful tool to personalize risk assessment. This study represents a patient-level pooled analysis of 6,139 patients undergoing PCI with stent implantation for ACS in the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) and ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trials who were randomized to treatment with bivalirudin versus heparin plus a glycoprotein IIb/IIIa inhibitor. The cohort was randomly divided into a risk score development cohort (n = 4,093) and a validation cohort (n = 2,046). Cox regression methods were used to identify clinical, angiographic, and procedural characteristics associated with Academic Research Consortium-defined definite/probable ST at 1 year. Each covariate in this model was assigned an integer score based on the regression coefficients. Variables included in the risk score were type of ACS (ST-segment elevation myocardial infarction, non-ST-segment elevation ACS with ST deviation, or non-ST-segment elevation ACS without ST changes), current smoking, insulin-dependent diabetes mellitus, prior PCI, baseline platelet count, absence of early (pre-PCI) anticoagulant therapy, aneurysmal/ulcerated lesion, baseline TIMI (Thrombolysis In Myocardial Infarction) flow grade 0/1, final TIMI flow grade <3, and number of treated vessels. Risk scores 1 to 6 were considered low risk, 7 to 9 intermediate risk, and 10 or greater high risk for ST. Rates of ST at 1 year in low-, intermediate-, and high-risk categories were 1.36%, 3.06%, and 9.18%, respectively, in the development cohort (p for trend <0.001), and 1.65%, 2.77%, and 6.45% in the validation cohort (p for trend = 0.006). The C-statistic for this risk score was over 0.65 in both cohorts. The individual risk of ST can be predicted using a simple risk score based on clinical, angiographic, and procedural variables. (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI]; NCT00433966) (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes [ACUITY]; NCT00093158).

Everolimus-eluting stent versus bare-metal stent in ST-segment elevation myocardial infarction (EXAMINATION): 1 year results of a randomised controlled trial

Article

Aug 2012
LANCET

Background: Everolimus-eluting stent (EES) reduces the risk of restenosis in elective percutaneous coronary intervention. However, the use of drug-eluting stent in patients with ST-segment elevation myocardial infarction (STEMI) is still controversial. Data regarding the performance of second-generation EES in this setting are scarce. We report the 1-year result of the EXAMINATION (clinical Evaluation of the Xience-V stent in Acute Myocardial INfArcTION) trial, comparing EES with bare-metal stents (BMS) in patients with STEMI. Methods: This multicentre, prospective, randomised, all-comer controlled trial was done in 12 medical centres in three countries. Between Dec 31, 2008, and May 15, 2010, we recruited patients with STEMI up to 48 h after the onset of symptoms requiring emergent percutaneous coronary intervention. Patients were randomly assigned (ratio 1:1) to receive EES or BMS. Randomisation was in blocks of four or six patients, stratified by centre and centralised by telephone. Patients were masked to treatment. The primary endpoint was the patient-oriented combined endpoint of all-cause death, any recurrent myocardial infarction, and any revascularisation at 1 year and was analysed by intention to treat. The secondary endpoints of the study included the device-oriented combined endpoint of cardiac death, target vessel myocardial infarction or target lesion revascularisation, and rates of all cause or cardiac death, recurrent myocardial infarction, target lesion or target vessel revascularisation, stent thrombosis, device and procedure success, and major and minor bleeding. This trial is registered with ClinicalTrials.gov, number NCT00828087. Findings: Of the 1504 patients randomised, 1498 patients were randomly assigned to receive EES (n=751) or BMS (n=747). The primary endpoint was similar in both groups (89 [11·9%] of 751 patients in the EES group vs 106 [14·2%] of 747 patients in the BMS group; difference -2·34 [95% CI -5·75 to 1·07]; p=0·19). Device-oriented endpoint (44 [5·9%] in the EES group vs 63 [8·4%] in the BMS group; difference -2·57 [95% CI -5·18 to 0·03]; p=0·05) did not differ between groups, although rates of target lesion and vessel revascularisation were significantly lower in the EES group (16 [2·1%] vs 37 [5·0%], p=0·003, and 28 [3·7%] vs 51 [6·8%], p=0·0077, respectively). Rates of all cause (26 [3·5%] for EES vs 26 [3·5%] for BMS, p=1·00) or cardiac death (24 [3·2%] for EES vs 21 [2·8%] for BMS, p=0·76) or myocardial infarction (10 [1·3%] vs 15 [2·0%], p=0·32) did not differ between groups. Stent thrombosis rates were significantly lower in the EES group (4 [0·5%] patients with definite stent thrombosis in the EES group vs 14 [1·9%] in the BMS group and seven [0·9%] patients with definite or probable stent thrombosis in the EES group vs 19 [2·5%] in the BMS group, both p=0·019). Although device success rate was similar between groups, procedure success rate was significantly higher in the EES group (731 [97·5%] vs 705 [94·6%]; p=0·0050). Finally, Bleeding rates at 1 year were comparable between groups (29 [3·9%] patients in the EES group vs 39 [5·2%] in the BMS group; p=0·19). Interpretation: The use of EES compared with BMS in the setting of STEMI did not lower the patient-oriented endpoint. However, at the stent level both rates of target lesion revascularisation and stent thrombosis were reduced in recipients of EES. Funding: Spanish Heart Foundation.

Blood and tissue compatibility of modified polyester: Thrombosis, inflammation, and healing

Article

Feb 1998
J Biomed Mater Res

Poly(ethylene terephthalate) (PET) has been reported in literature to be moderately inflammatory and thrombogenic. To moderate the inflammatory response, PET fabric was surface modified by either Fluoropassiv™ fluoropolymer (FC), or an RGD-containing peptide (RGD). Samples were subsequently autoclave sterilized and implanted subcutaneously in Sprague Dawley rats for 2 to 4 weeks. Retrieved samples were evaluated histopathologically for indications of material toxicity and healing. Minimal acute or chronic inflammation was associated with the fabrics after 2 and 4 week implant duration. However, fibroblast proliferation into FC modified fabric (PET/FC) was less than that into unmodified (PET) and RGD modified fabric (PET/RGD) after 4 weeks, suggesting that FC modification of PET may inhibit excessive tissue growth. Additional samples of modified and unmodified fabrics were placed in stainless steel mesh cages, which were then implanted subcutaneously for 4 weeks. Cellular exudate was extracted weekly and cell concentrations within the exudate measured. Total leukocyte count (TLC) (reflective of local inflammation) at 1 week for PET/RGD was greater than that for PET/FC and PET. TLCs after 4 week implant decreased for all sample groups. In a separate experiment, PET vascular grafts surface modified by either FC or RGD were contacted 1h with blood using the baboon arteriovenous (AV) shunt model of thrombosis in both the presence and absence of heparin. Accumulation of 111In labeled platelets (reflective of thrombus accumulation) upon grafts was less in the presence of heparin (effect significant at p = 1.2 × 10−6, two-way ANOVA). Accumulation (in the presence of heparin) upon PET/RGD was less (p = 0.19), and upon PET/FC significantly less (p = 0.016) than that upon the unmodified PET control, suggesting that FC modification of PET may inhibit thrombus accumulation. © 1998 John Wiley & Sons, Inc. J Biomed Mater Res, 39, 130–140, 1998.

Stent thrombosis with drug-eluting and bare-metal stents: Evidence from a comprehensive network meta-analysis

Article

Mar 2012
LANCET

The relative safety of drug-eluting stents and bare-metal stents, especially with respect to stent thrombosis, continues to be debated. In view of the overall low frequency of stent thrombosis, large sample sizes are needed to accurately estimate treatment differences between stents. We compared the risk of thrombosis between bare-metal and drug-eluting stents. For this network meta-analysis, randomised controlled trials comparing different drug-eluting stents or drug-eluting with bare-metal stents currently approved in the USA were identified through Medline, Embase, Cochrane databases, and proceedings of international meetings. Information about study design, inclusion and exclusion criteria, sample characteristics, and clinical outcomes was extracted. 49 trials including 50,844 patients randomly assigned to treatment groups were analysed. 1-year definite stent thrombosis was significantly lower with cobalt-chromium everolimus eluting stents (CoCr-EES) than with bare-metal stents (odds ratio [OR] 0·23, 95% CI 0·13-0·41). The significant difference in stent thrombosis between CoCr-EES and bare-metal stents was evident as early as 30 days (OR 0·21, 95% CI 0·11-0·42) and was also significant between 31 days and 1 year (OR 0·27, 95% CI 0·08-0·74). CoCr-EES were also associated with significantly lower rates of 1-year definite stent thrombosis compared with paclitaxel-eluting stents (OR 0·28, 95% CI 0·16-0·48), permanent polymer-based sirolimus-eluting stents (OR 0·41, 95% CI 0·24-0·70), phosphorylcholine-based zotarolimus-eluting stents (OR 0·21, 95% CI 0·10-0·44), and Resolute zotarolimus-eluting stents (OR 0·14, 95% CI 0·03-0·47). At 2-year follow-up, CoCr-EES were still associated with significantly lower rates of definite stent thrombosis than were bare-metal (OR 0·35, 95% CI 0·17-0·69) and paclitaxel-eluting stents (OR 0·34, 95% CI 0·19-0·62). No other drug-eluting stent had lower definite thrombosis rates compared with bare-metal stents at 2-year follow-up. In randomised studies completed to date, CoCr-EES has the lowest rate of stent thrombosis within 2 years of implantation. The finding that CoCr-EES also reduced stent thrombosis compared with bare-metal stents, if confirmed in future randomised trials, represents a paradigm shift. The Cardiovascular Research Foundation.

Intravascular Ultrasound Findings of Early Stent Thrombosis After Primary Percutaneous Intervention in Acute Myocardial Infarction A Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Substudy

Article

Jun 2011

Small stent area and residual inflow/outflow disease have been reported as the strongest intravascular ultrasound (IVUS) predictors of early stent thrombosis (ST) in patients with stable angina. IVUS predictors of early ST in patients with acute myocardial infarction have not been studied. In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) study, a formal substudy included poststent and 13-month follow-up IVUS at 36 centers. Twelve patients with baseline IVUS who had definite/probable early ST ≤30 days after enrollment were compared with 389 patients without early ST. Significant residual stenosis was a lumen area <4.0 mm(2) with ≥70% plaque burden ≤10 mm from each stent edge. Significant edge dissection was more than medial dissection with lumen area <4 mm(2) or dissection angle ≥60°. Randomization to bivalirudin (P=0.29) or paclitaxel-eluting stent (P=0.74) was not related to early ST. Minimum lumen area was smaller in patients with versus without early ST (4.4 mm(2) [3.6, 6.9] versus 6.7 mm(2) [5.3, 8.0], respectively, P=0.014). Minimum lumen area <5 mm(2), significant residual stenosis, significant stent edge dissection, and significant tissue (plaque/thrombus) protrusion (more than the median that narrowed the lumen to <4 mm(2)) were more prevalent in patients with early ST, but significant acute malapposition (more than the median) was not. Overall, 100% of patients with early ST had at least 1 of these significant features: minimum lumen area <5 mm(2), edge dissection, residual stenosis, or tissue protrusion versus 23% in patients without early ST (P<0.01). Smaller final lumen area and inflow/outflow disease (residual stenosis or dissection) but not acute malapposition were related to early ST after acute myocardial infarction intervention. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00433966.

A method to develop mock arteries suitable for cell seeding and in-vitro cell culture experiments

Article

Aug 2010

Sylgard((R)) is a biocompatible elastomer which has been widely used in biomedical applications including in simulations of the mechanical response of soft tissues and mechanotransduction investigations. In this study the effect of fabrication parameters including base to curing agent ratio and curing time on the mechanical response of Sylgard((R)) was investigated and a novel fabrication technique for the production of mock arteries with highly uniform thickness, which is essential for mechanotransduction studies, is described. Finally a method for the surface treatment of Sylgard((R)) using sulphuric acid and fibronectin to enhance smooth muscle cell (SMC) adhesion is proposed and examined in vitro. Sylgard((R)) mock coronary arteries fabricated using the proposed technique exhibited a mechanical response close to arterial tissue with cell adhesion enhanced using the surface treatment techniques described.

The Risk of Stent Thrombosis in Patients With Acute Coronary Syndromes Treated With Bare-Metal and Drug-Eluting Stents

Article

Jul 2009

We aimed to evaluate the risk of definite stent thrombosis with bare-metal stents (BMS) and drug-eluting stents (DES) in patients treated for acute coronary syndromes. Acute coronary syndromes (ACS) have been reported as increasing the risk for stent thrombosis. Between January 2000 and December 2005, 5,816 consecutive patients underwent percutaneous coronary intervention for de novo lesions with a single stent type. These patients consisted of 3 sequential groups of BMS (n = 2,248), sirolimus-eluting stents (n = 822) and paclitaxel-eluting stents (n = 2,746). In total, 3,485 patients presented with an ACS. After a median follow-up of 1,394 days, patients with ACS had a definite stent thrombosis rate of 2.5% versus 1.0% in patients with stable angina (propensity score-adjusted hazard ratio [HR]: 2.80, 95% confidence interval [CI]: 1.72 to 4.56). ACS patients had a higher risk of early and late stent thrombosis, although the increased risk of very late stent thrombosis was only present in ACS patients treated with DES. In stable patients, any stent thrombosis resulted in a significant increase in mortality (adjusted HR: 4.0, 95% CI: 1.7 to 9.3), although this was particularly evident for late or very late stent thrombosis; in contrast only early stent thrombosis significantly increased mortality in patients with acute coronary syndrome patients (adjusted HR: 2.0, 95% CI: 1.0 to 4.1). Patients with acute coronary syndromes are at higher risk of early and late stent thrombosis with either BMS or DES, although very late stent thrombosis seems to be uniquely associated with DES. The clinical sequelae of late and very late stent thrombosis are more pronounced in stable patients.

Early Stent Thrombosis in Patients With Acute Coronary Syndromes Treated With Drug-Eluting and Bare Metal Stents The Acute Catheterization and Urgent Intervention Triage Strategy Trial

Article

Feb 2009
CIRCULATION

The clinical and angiographic predictors of early (<30 days) stent thrombosis (ST) have not been reported in high-risk patients with acute coronary syndromes. Qualitative and quantitative coronary angiographic analyses were performed in 3405 patients with moderate- and high-risk acute coronary syndromes in whom stents were implanted in the prospective randomized Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial, including 3043 patients (89.4%) in whom drug-eluting stents were implanted. Within 30 days, definite or probable ST occurred in 48 patients (1.4%). ST rates were not significantly different in patients treated with bare metal stents compared with drug-eluting stents (1.4% versus 1.4%; P=1.00) or with heparin plus glycoprotein IIb/IIIa inhibitors (1.1%) compared with bivalirudin with or without IIb/IIIa inhibitors (1.6% and 1.5%, respectively; P=0.26 and P=0.37, respectively). Compared with patients without ST, patients with ST more frequently had insulin-requiring diabetes mellitus and baseline renal insufficiency, a greater overall burden of coronary atherosclerosis, and suboptimal final angiographic results. ST also was more common in patients without preprocedural thienopyridine administration and with inconsistent antiplatelet drug use within 30 days. By multivariable analysis, the strongest independent predictors of definite ST were a smaller final stent minimal lumen diameter, a lack of preprocedural thienopyridine administration, the extent of coronary artery disease, and higher baseline hemoglobin level. Occurring in nearly 1 in 70 patients, early ST is relatively common in acute coronary syndromes, occurs with similar frequency after anticoagulation with either heparin plus glycoprotein IIb/IIIa inhibitors or bivalirudin with or without IIb/IIIa inhibitors, and is predicted by diffuse atherosclerosis, suboptimal angiographic results, and inadequate pharmacotherapy.

Neutrophil, Not Macrophage, Infiltration Precedes Neointimal Thickening in Balloon-Injured Arteries

Article

Dec 2000
ARTERIOSCL THROM VAS

Macrophages are abundant after stent-induced arterial injury. Inhibition of macrophage recruitment blocks neointimal growth in this model. In contrast, after superficial injury from balloon endothelial denudation, macrophages are sparse. However, many anti-inflammatory therapies remain effective against neointimal growth after balloon injury. To investigate further the role of leukocytes after injury, 41 New Zealand White rabbits underwent iliac artery balloon denudation. In 18, subcutaneous pumps were placed to deliver intravenous heparin (0.3 mg/kg per hour). Arteries were harvested at 6 hours and at 3, 7, and 14 days. In 8 animals, either M1/70 (a monoclonal antibody [mAb] against adhesion molecule Mac-1) or a nonspecific IgG was given (5 mg/kg IV bolus and then 1 mg/kg SC QOD), and arteries were harvested at 6 hours and 3 days. Computer-aided morphometry was performed as was immunohistochemistry to assess smooth muscle cell (SMC) proliferation (bromodeoxyuridine-positive cells), neutrophil content (RPN357, mAb against rabbit neutrophil/thymocyte), and macrophage content (RAM-11, mAb against rabbit macrophage). Heparin inhibited neointimal growth at 7 and 14 days (64% and 32.5% reduction, respectively; P:<0.05). Neutrophils were observed in the media early after balloon injury, and heparin and M1/70 inhibited this infiltration (82% and 83% reduction, respectively; P:<0.05 each) with a coincident inhibition of medial SMC proliferation at 3 days (49% and 84% reduction, respectively; P:<0.05 each). Macrophages were absent at all time points. Neutrophil, but not macrophage, infiltration occurs early after endothelial denudation. Inhibition of this process is associated with a reduction in medial SMC proliferation. These data suggest a central role for neutrophils in restenosis and help to explain prior reports of an inhibitory effect of anti-inflammatory therapies on neointimal growth after balloon injury.

Intracoronary Stenting and Angiographic Results : Strut Thickness Effect on Restenosis Outcome (ISAR-STEREO) Trial

Article

Jun 2001
CIRCULATION

Increased thrombogenicity and smooth muscle cell proliferative response induced by the metal struts compromise the advantages of coronary stenting. The objective of this randomized, multicenter study was to assess whether a reduced strut thickness of coronary stents is associated with improved follow-up angiographic and clinical results. A total of 651 patients with coronary lesions situated in native vessels >2.8 mm in diameter were randomly assigned to receive 1 of 2 commercially available stents of comparable design but different thickness: 326 patients to the thin-strut stent (strut thickness of 50 microm) and 325 patients to the thick-strut stent (strut thickness of 140 microm). The primary end point was the angiographic restenosis (>/=50% diameter stenosis at follow-up angiography). Secondary end points were the incidence of reinterventions due to restenosis-induced ischemia and the combined rate of death and myocardial infarctions at 1 year. The incidence of angiographic restenosis was 15.0% in the thin-strut group and 25.8% in the thick-strut group (relative risk, 0.58; 95% CI, 0.39 to 0.87; P=0.003). Clinical restenosis was also significantly reduced, with a reintervention rate of 8.6% among thin-strut patients and 13.8% among thick-strut patients (relative risk, 0.62; 95% CI, 0.39 to 0.99; P=0.03). No difference was observed in the combined 1-year rate of death and myocardial infarction. The use of a thinner-strut device is associated with a significant reduction of angiographic and clinical restenosis after coronary artery stenting. These findings may have relevant implications for the currently most widely used percutaneous coronary intervention.

Morphological Predictors of Restenosis After Coronary Stenting in Humans

Article

Jun 2002
CIRCULATION

Experimental studies suggest that arterial injury and inflammation lead to increased neointimal growth after stenting. Despite the increased use of coronary stents in humans, there are only limited pathological data on the morphological features of in-stent restenosis. Detailed histology was performed on 116 stents, implanted > or =90 days in 87 coronary arteries, from 56 patients (mean age, 59+/-13 years). The mean duration of stent implant was 10 months. In-stent restenosis was defined as a stent area stenosis of >75%. Lumen area increased as stent area increased (r2=0.27, P=0.0001), but there was a much stronger correlation between stent area and neointimal area (r2=0.70, P<0.0001). Arterial medial fracture was associated with a 29% increase (P<0.01) in neointimal thickness compared with arteries with an intact media. Neointimal thickness (P=0.0001), inflammatory cell density (P<0.0001), and neointimal vascular channel density (P<0.0001) were greater when struts were in contact with a ruptured arterial media compared with fibrous plaque or an intact fibrous cap. Stent strut penetration into a lipid core was associated with increased neointimal thickness (P=0.04) and inflammatory cell density (P=0.03). Neointimal inflammatory cell content was 2.4-fold greater in stents with restenosis versus no restenosis, and inflammation was associated with increased neoangiogenesis. Coronary stenting that is accompanied by medial damage or penetration of the stent into a lipid core induces increased arterial inflammation, which is associated with increased neointimal growth. These data suggest the use of stenting strategies that reduce inflammation and neoangiogenesis to reduce the incidence of restenosis.

Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent implantation

Article

Apr 2005
J AM COLL CARDIOL

We sought to determine the real-world incidence of angiographically confirmed and possible stent thrombosis (ST) in an unrestricted population during the first 30 days after bare-metal stent (BMS), sirolimus-eluting stent (SES), and paclitaxel-eluting stent (PES) implantation. Current data on ST in drug-eluting stents (DES) have come from randomized trials with strict entry criteria, which limits their generalizability to daily practice. The study population comprised three sequential cohorts of 506 consecutive patients with BMS, 1,017 consecutive patients with SES, and 989 consecutive patients treated with PES. In the first 30 days after stent implantation, 6 BMS (1.2%, 95% confidence interval [CI] 0.5% to 2.6%; p = 0.9), 10 SES (1.0%, 95% CI 0.5% to 1.8%), and 10 PES (1.0%, 95% CI 0.6% to 1.9%) patients developed angiographically proven ST. Multiple potential risk factors were identified in most patients with ST. Bifurcation stenting in the setting of acute myocardial infarction was an independent risk factor for angiographic ST in the entire population (odds ratio [OR] 12.9, 95% CI 4.7 to 35.8, p < 0.001). In patients with DES who had angiographic ST, 30-day mortality was 15%, whereas another 60% suffered a nonfatal myocardial infarction; no further deaths occurred during six months of follow-up. Including possible cases, 7 BMS (1.4%, 95% CI 0.7% to 2.8%), 15 SES (1.5%, 95% CI 0.9% to 2.4%), and 16 PES (1.6%, 95% CI 1.0% to 2.6%) patients had ST. The unrestricted use of SES or PES is associated with ST rates in the range expected for BMS. Stent thrombosis was associated with a high morbidity and mortality. Bifurcation stenting, when performed in patients with acute myocardial infarction, was associated with an increased risk of ST.

Simultaneous Inference in General Parametric Models

Article

Jun 2008
BIOMETRICAL J

Simultaneous inference is a common problem in many areas of application. If multiple null hypotheses are tested simultaneously, the probability of rejecting erroneously at least one of them increases beyond the pre-specified significance level. Simultaneous inference procedures have to be used which adjust for multiplicity and thus control the overall type I error rate. In this paper we describe simultaneous inference procedures in general parametric models, where the experimental questions are specified through a linear combination of elemental model parameters. The framework described here is quite general and extends the canonical theory of multiple comparison procedures in ANOVA models to linear regression problems, generalized linear models, linear mixed effects models, the Cox model, robust linear models, etc. Several examples using a variety of different statistical models illustrate the breadth of the results. For the analyses we use the R add-on package multcomp, which provides a convenient interface to the general approach adopted here.

Acute Thrombogenicity of a Durable Polymer Everolimus-Eluting Stent Relative to Contemporary Drug-Eluting Stents With Biodegradable Polymer Coatings Assessed Ex Vivo in a Swine Shunt Model

Abstract

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