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Background The BIONICS (BioNIR Ridaforolimus‐Eluting Coronary Stent System in Coronary Stenosis) and the NIREUS (BioNIR Ridaforolimus Eluting Coronary Stent System [BioNIR] European Angiography Study) randomized clinical trials showed noninferiority of the ridaforolimus‐eluting stent (RES) compared with the zotarolimus‐eluting stent (ZES) with respect to 1‐year target‐lesion failure and 6‐month angiographic late lumen loss. We aimed to evaluate clinical outcomes between treatment groups over a 5‐year follow‐up. Methods and Results Patient‐level data from the BIONICS (n=1919) and NIREUS (n=302) were pooled, comparing the outcomes of patients implanted with RES and ZES. The primary end point was the 5‐year rate of target‐lesion failure. A total of 2221 patients (63.2±10.3 years, 79.7% men) undergoing percutaneous coronary intervention with RES (n=1159) or ZES (n=1062) were included. Most clinical and angiographic characteristics were similar between groups. At 5 years, the primary end point of target‐lesion failure was similar between treatment groups (12.2% RES versus 11.3% ZES, P=0.52). Rates of TLR (7.6% RES versus 6.8% ZES, P=0.42) target‐vessel–related myocardial infarction (4.8% RES versus 4.9% ZES, P=0.95) and stent thrombosis (0.9% RES versus 0.9% ZES, P=0.87) also did not differ between groups. Target‐vessel revascularization and cardiac death were higher among the RES group (12.3% versus 9.5% P=0.037, and 3.6% versus 2.2% P=0.042, respectively). However, after correction for baseline characteristics, there was no significant difference in cardiac death between groups. Conclusions In a pooled analysis of 2 randomized trials, 5‐year clinical outcomes were similar between patients undergoing percutaneous coronary intervention with RES and ZES. These results support the long‐term safety and efficacy of RES for the treatment of patients with coronary artery disease.

Zotarolimus (ABT-578) is a sirolimus derivative that, like sirolimus and everolimus, is an inhibitor of cell growth via inhibition of the mechanistic target of rapamycin (mTOR). Zotarolimus was developed for coating coronary stents to prevent smooth muscle cell proliferation and restenosis. Albeit zotarolimus-eluting cardiovascular devices have been on the market for years, details of zotarolimus drug metabolism in humans are still unknown. Hence, it was the goal of the present study to identify zotarolimus metabolites generated by incubation with human liver microsomes. Metabolite structures were identified using high-resolution mass spectrometry, MS/ion-trap (MSn), and comparison of fragmentation patterns of the metabolites with those of zotarolimus and other known sirolimus derivatives. Kinetic parameters such as incubation time, human liver microsomal protein concentrations, and drug concentrations were optimized before scaling up the metabolism experiments. Human liver microsomes mainly hydroxylated and/or demethylated zotarolimus. The structures of the following metabolites were identified: O-demethylated metabolites: 39-O-desmethyl, 16-O-desmethyl, and 27-O-desmethyl zotarolimus; hydroxylated metabolites: hydroxy piperidine zotarolimus, 11-hydroxy, 12-hydroxy, 14-hydroxy, 23-hydroxy, 24-hydroxy, 25-hydroxy, 45/46-hydroxy, and 49-hydroxy zotarolimus; demethylated-hydroxylated metabolites: 16-O-desmethyl, 23/24-hydroxy; 39-O-desmethyl, 23/24-hydroxy; 39-O-desmethyl, 25-hydroxy zotarolimus; 39-O-desmethyl, 11-hydroxy zotarolimus; 39-O-desmethyl, hydroxy-piperidine zotarolimus; 27-O-desmethyl, 45/46-hydroxy zotarolimus; didemethylated metabolites: 16,39-O-didesmethyl zotarolimus; 16,27-O-didesmethyl zotarolimus; 27,39-O-didesmethyl zotarolimus; and dihydroxylated metabolites: 11,24-dihydroxy zotarolimus, 12,24-dihydroxy zotarolimus, and 11,47/48-dihydroxy zotarolimus. It is concluded that zotarolimus is extensively metabolized by human liver microsomes. Twenty-four of these metabolites could be structurally identified using a combination of ion-trap MSn and high-resolution mass spectrometry. [ABSTRACT FROM AUTHOR]

Zotarolimus (ABT-578) is a sirolimus derivative that, like sirolimus and everolimus, is an inhibitor of cell growth via inhibition of the mechanistic target of rapamycin (mTOR). Zotarolimus was developed for coating coronary stents to prevent smooth muscle cell proliferation and restenosis. Albeit zotarolimus-eluting cardiovascular devices have been on the market for years, details of zotarolimus drug metabolism in humans are still unknown. Hence, it was the goal of the present study to identify zotarolimus metabolites generated by incubation with human liver microsomes. Metabolite structures were identified using high-resolution mass spectrometry, MS/ion-trap (MSn), and comparison of fragmentation patterns of the metabolites with those of zotarolimus and other known sirolimus derivatives. Kinetic parameters such as incubation time, human liver microsomal protein concentrations, and drug concentrations were optimized before scaling up the metabolism experiments. Human liver microsomes mainly hydroxylated and/or demethylated zotarolimus. The structures of the following metabolites were identified: O-demethylated metabolites: 39-O-desmethyl, 16-O-desmethyl, and 27-O-desmethyl zotarolimus; hydroxylated metabolites: hydroxy piperidine zotarolimus, 11-hydroxy, 12-hydroxy, 14-hydroxy, 23-hydroxy, 24-hydroxy, 25-hydroxy, 45/46-hydroxy, and 49-hydroxy zotarolimus; demethylated-hydroxylated metabolites: 16-O-desmethyl, 23/24-hydroxy; 39-O-desmethyl, 23/24-hydroxy; 39-O-desmethyl, 25-hydroxy zotarolimus; 39-O-desmethyl, 11-hydroxy zotarolimus; 39-O-desmethyl, hydroxy-piperidine zotarolimus; 27-O-desmethyl, 45/46-hydroxy zotarolimus; didemethylated metabolites: 16,39-O-didesmethyl zotarolimus; 16,27-O-didesmethyl zotarolimus; 27,39-O-didesmethyl zotarolimus; and dihydroxylated metabolites: 11,24-dihydroxy zotarolimus, 12,24-dihydroxy zotarolimus, and 11,47/48-dihydroxy zotarolimus. It is concluded that zotarolimus is extensively metabolized by human liver microsomes. Twenty-four of these metabolites could be structurally identified using a combination of ion-trap MSn and high-resolution mass spectrometry.

Background: little researches have directly compared second-generation drug-eluting stents with each other or with bare-metal stents. Aim of the work: To compare between outcomes after implantation of bare-metal stents [BMS] and two kinds of 2nd generation drug eluting stents [DES] [Zotarolimus-Eluting Stents [ZES], and A Everolimus-Eluting Stents [EES]] in patients undergoing percutaneous coronary intervention. Patients and Methods: 160 Ischemic Heart Disease [IHD] patients undergoing PCI with 2nd generation DES implantation [80 ZES and 80 EES] were analyzed against 50 IHD patients undergoing PCI with BMS implantation. Each patients group received up to 6 [in BMS group] or 24 months [in ZES and EES groups] of clopidogrel therapy. The key efficacy endpoint was the 24 months major adverse cardiac event [MACE] [death, myocardial infarction, or target lesion revascularization], whereas stent thrombosis [ST] was the safety endpoint. Results: The MACE rate was lowest in EES [19%; χ2= 7.661], highest in BMS [41.7%; χ2 =7.661], and intermediate in ZES [28.2%; χ2= 7.661] group with significant P Value =0.002.The 2-year incidence of ST in the EES group [1.3%] was similar to that in the ZES-S group [2.2%], whereas it was lower in contrast with BMS [7.5%] groups, with significant P value= 0.004]. Conclusion: DES have more efficacy and safety than BMS as EES have lowest MACE and ST rate while BMS have the highest rate and ZES have intermediate rate while the three stent groups have similar rate of mortality at 2 years follow up.

Objective: There is a scarcity of comparative studies between Endeavor Resolute®-zotarolimus-eluting stent (R-ZES) and Resolute Integrity®-ZES (I-ZES) during long-term follow-up periods. Although the stent alloy and the polymer of these two ZESs are similar, the platform and the design of these two stents are different. This study was conducted to compare the efficacy and safety of these two different ZESs in the all-comer Korean patients who underwent percutaneous coronary intervention (PCI) during a 3-year follow-up period. Methods: This study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. In this single-center, retrospective, and all-comer patients' cohort study, a total of 889 patients who underwent PCI with R-ZES (n=394) or I-ZES (n=495) were enrolled. The primary endpoint was the occurrence of major adverse cardiac events (MACEs) defined as all-cause death, nonfatal myocardial infarction (MI), any repeat revascularization including target lesion revascularization (TLR), target vessel revascularization (TVR), and non-TVR, and the secondary endpoint was stent thrombosis (ST) at 3 years. Results: To adjust for any potential confounders, the propensity score-adjusted multivariable analysis was performed using the logistic regression model (C-statistics=0.689). The cumulative incidence rates of MACEs [adjusted hazard ratio (aHR), 1.341; 95% confidence interval (CI), 0.615–2.922; p=0.461], all-cause death, nonfatal MI, any repeat revascularization, and ST (aHR, 2.090; 95% CI, 0.163–26.77; p=0.571) were similar between the two groups during the 3-year follow-up period. Conclusion: R-ZES and I-ZES demonstrated comparable efficacy and safety after PCI during a 3-year follow-up period. However, these results can perhaps be more precisely defined by other large and long-term follow-up studies in the future. (Anatol J Cardiol 2020; 23: 268-76)

Background: Very long-term outcomes according to diabetic status of patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) with new-generation drug-eluting stents (DES) are scant. Both, the durable polymer zotarolimus-eluting stent (DP-ZES), the first DES to gain FDA-approval for specific use in patients with diabetes mellitus, and the polymer-free sirolimus- and probucol-eluting stent (PF-SES), with a unique design that enables effective drug release without the need of a polymer offer the potential to enhance clinical long-term outcomes especially in patients with diabetes mellitus. Methods: We investigate 10-year clinical outcomes of the prespecified subgroups of patients with and without diabetes mellitus, randomly assigned to treatment with PF-SES versus DP-ZES in the ISAR-TEST 5 trial. The primary endpoint of interest was major adverse cardiac events (MACE), defined as the composite of all-cause death, any myocardial infarction or any revascularization. Further endpoints of interest were cardiac death, myocardial infarction related to the target vessel and target lesion revascularization as well as the individual components of the primary composite endpoint and the incidence of definite or probable stent thrombosis at 10 years. Results: This analysis includes a total of 3002 patients randomly assigned to PF-SES (n = 2002) or DP-ZES (n = 1000). Prevalence of diabetes mellitus was high and comparable, 575 Patients (28.7%) in PF-SES group and 295 patients (29.5%) in DP-ZES group (P = 0.66). At 10 years 53.5% of patients with diabetes mellitus and 68.5% of patients without diabetes mellitus were alive. Regarding major adverse cardiac events, PF-SES as compared to DP-ZES showed comparable event rates in patients with diabetes mellitus (74.8% vs. 79.6%; hazard ratio 0.86; 95% CI 0.73–1.02; P = 0.08) and in patients without diabetes (PF-SES 62.5% vs. DP-ZES 62.2%; hazard ratio 0.99; 95% CI 0.88–1.11; P = 0.88). Conclusion: At 10 years, both new-generation DES show comparable clinical outcome irrespective of diabetic status or polymer strategy. Event rates after PCI in patients with diabetes mellitus are considerable higher than in patients without diabetes mellitus and continue to accrue over time. Trial registration: ClinicalTrials.gov, NCT00598533, Registered 10 January 2008, https://clinicaltrials.gov/ct2/show/NCT00598533?term=NCT00598533 Kaplan-Meier estimates of endpoints of interest for patients with vs. without diabetes mellitus treated with PF-SES vs. DP-ZES. Bar graphs: Kaplan-Meier estimates as percentages. PF-SES: polymer-free sirolimus-eluting stent; DP-ZES: durable polymer zotarolimus-eluting stent; DM: diabetes mellitus. Comparison of event rates of individual endpoints in patients with and without diabetes mellitus treated with PF-SES vs. DP-ZES all without statistically significant differences. Comparison of event rates of individual endpoints in overall patients with vs. without diabetes mellitus significantly different (P ≤ 0.01 for all comparisons). [ABSTRACT FROM AUTHOR]

Background: Endeavor®-zotarolimus-eluting stent (E-ZES) was the first ZES to be developed, and Resolute integrity®-ZES (I-ZES) has been developed more recently. Comparative studies on long-term usage of these two ZESs have been rare. Objectives: The aim of this study was to compare the efficacy and safety of E-ZES and I-ZES during a long-term follow-up of patients who underwent percutaneous coronary intervention (PCI). Methods: A total of 767 patients who underwent PCI with E-ZES or I-ZES were eligible for this study. The primary endpoint was the occurrence of major adverse cardiac events (MACEs), defined as the composite of all-cause death, non-fatal myocardial infarction (MI), and any repeat revascularization. The secondary endpoint was stent thrombosis (ST). Results: After propensity score-matched (PSM) analysis, two PSM groups (193 pairs, n = 386, C-statistic = 0.824) were generated. During the 3-year follow-up period, the cumulative inci­dence of MACEs (hazard ratio [HR], 0.837; 95% confidence interval [CI], 0.464–1.508; p = 0.553) and ST (HR, 0.398; 95% CI, 0.077–2.052; p = 0.271) was similar for the E-ZES and I-ZES groups. Additionally, the cumulative incidences of all-cause death, cardiac death, non-fatal MI, and any repeat revascularization were not significantly different between the two groups. Conclusions: Although I-ZES utilizes a more advanced stent platform, stent design, and polymer system than E-ZES, both the ZESs showed comparable efficacy and safety during the 3-year follow-up period in this single-center, all-comers registry. However, further large-scaled, randomized, well-controlled trials with long-term follow-up are needed to verify these results.

Introduction: Local treatment of the airways and lung parenchyma has been used in clinical practice for several years for a variety of diseases. Methods: A variety of endoscopic tools for local treatment exist, especially for treating malignancies. Using these endoscopic tools, one can administer drugs specifically designed for the airways. Discussion: This article presents all locally administered treatment options and provides useful insights for future local endoscopically applied treatments.

Background: Outcome data after extended long-term follow-up of patients with coronary artery disease treated with drug-eluting stents (DES) in randomized clinical trials are scant.Objectives: Performance differences among devices may be expected to emerge over time depending on whether stenting is done with polymer-free or durable polymer DES. This study assessed the 10-year outcomes of patients enrolled in the ISAR-TEST-5 (Test Efficacy of Sirolimus- and Probucol-Eluting Versus Zotarolimus-Eluting Stents) trial.Methods: A total of 3,002 patients were randomized to treatment with either polymer-free sirolimus- and probucol-eluting stents (n = 2,002) or durable polymer zotarolimus-eluting stents (n = 1,000). The primary endpoint was the composite of cardiac death, target vessel-related myocardial infarction, or target lesion revascularization (a device-oriented composite endpoint [DOCE]). Additional endpoints of interest were the patient-oriented composite endpoint (POCE), including all-cause death, any myocardial infarction, or any revascularization; individual components of the composite endpoints; and definite or probable stent thrombosis.Results: The median age of the patients at randomization was 67.8 years. At 10 years, 63.9% of patients were alive. The rates of DOCE and POCE were high in both groups with no difference in the incidence between polymer-free sirolimus- and probucol-eluting stents and durable polymer zotarolimus-eluting stents (DOCE: 43.8% vs. 43.0%, respectively; hazard ratio: 1.01; 95% confidence interval [CI]: 0.89 to 1.14; p = 0.90; POCE: 66.2% vs. 67.7%, respectively; hazard ratio: 0.94; 95% CI: 0.86 to 1.04; p = 0.22). The rates of the individual components of the composite endpoints were comparable in both groups. The incidence of definite/probable stent thrombosis over 10 years was low and comparable in both groups (1.6% vs. 1.9%; hazard ratio: 0.85; 95% CI: 0.46 to 1.54; p = 0.58).Conclusions: At 10 years, there were no measurable differences in outcomes between patients treated with polymer-free versus durable polymer DES. The incidence of stent thrombosis was low and comparable in both groups. High overall adverse clinical event rates were observed during extended follow-up. (Test Efficacy of Sirolimus- and Probucol-Eluting Versus Zotarolimus-Eluting Stents [ISAR-TEST-5]; NCT00598533). [ABSTRACT FROM AUTHOR]

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Zotarolimus is a semi-synthetic derivative of rapamycin and an inhibitor of mammalian target of rapamycin (mTOR) signaling. Currently, zotarolimus is used to prolong the survival time of organ grafts, but it is also a novel immunosuppressive agent with potent anti-proliferative activity. Here, we examine the anti-tumor effect of zotarolimus, alone and in combination with 5-fluorouracil, on HCT-116 colorectal adenocarcinoma cells implanted in BALB/c nude mice. Compared with the control mice, mice treated with zotarolimus or zotarolimus combined with 5-FU showed retarded tumor growth; increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase (ERK) phosphorylation; reduced inflammation-related factors such as IL-1β, TNF-α, and cyclooxygenase-2 (COX-2) protein; and inhibited metastasis-related factors such as CD44, epidermal growth factor receptor (EGFR), transforming growth factor β (TGF-β), and vascular endothelial growth factor (VEGF). Notably, mice treated with a combination of zotarolimus and 5-FU showed significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with mice treated with 5-FU or zotarolimus alone, indicating a strong synergistic effect. This in vivo study confirms that zotarolimus or zotarolimus combined with 5-FU can be used to retard colorectal adenocarcinoma growth and inhibit tumorigenesis. Our results suggest that zotarolimus may increase the chemo-sensitization of tumor cells. Therefore, zotarolimus alone and zotarolimus combined with 5-FU may be potential anti-tumor agents in the treatment of human colon adenocarcinoma. Future research on zotarolimus may lead to the development of new therapeutic strategies.

Purpose: We investigated the safety and efficacy of biodegradable polymer drug-eluting stents (BP-DES) versus second-generation durable polymer drug-eluting stents (DP-DES) in a follow-up period of 5 years. Methods: A meta-analysis was performed using data from the PubMed, EMBASE, and Cochrane Library databases. The primary endpoint was target lesion failure (TLF), a composite endpoint of safety and efficacy, which included cardiac death, target vessel myocardial infarction (MI), and clinically indicated target lesion revascularization (TLR). Secondary endpoints were all-cause death, MI, TLR, definite or probable stent thrombosis (ST), and definite or probable very late ST. In addition, we performed subgroup analyses based on patient and stent characteristics. Results: Nine randomized controlled trials (RCTs) in 11,817 patients were included in the meta-analysis. Compared with second-generation DP-DES, BP-DES was not associated with increased risk of TLF (odds ratio (OR) 1.06, 95 % confidence interval [CI] 0.94–1.20; p = 0.33), all-cause death (OR 1.04, [0.92–1.18], p = 0.49), myocardial infarction (OR 0.97, [0.83–1.13], p = 0.67), target lesion revascularization (OR 1.08, [0.94–1.23], p = 0.27), definite or probable stent thrombosis (OR 0.85, [0.66–1.11], p = 0.24), or definite or probable very late stent thrombosis (OR 0.86, [0.58–1.26],p = 0.43). Furthermore, the subgroup analyses did not reveal any statistically significant differences between the stent groups. Conclusion: At 5 years of follow-up, the safety and efficacy of BP-DES are clinically comparable to those of second-generation DP-DES. [ABSTRACT FROM AUTHOR]

Several new coronary stents have been, or soon will be, introduced in the United States. These stents incorporate certain characteristics, such as polymer-free drug coatings, ultrathin stent struts, bioresorbable polymers, and composite materials, that address currently unmet clinical needs to enhance acute stent performance, improve longer-term clinical outcomes, and obviate obligatory prolonged dual antiplatelet therapy. This article reviews the key and novel features of these stents. [ABSTRACT FROM AUTHOR]

Drug elution profiles must be studied in vitro to optimize a polymer-drug formulation during development of drug-eluting stents (DESs). Results from HPLC assays of drug contents and elution kinetics from a biodegradable sirolimus coating and a stable zotarolimus coating on coronary DESs are presented. Drug contents were assessed for crimped stents on the delivery system and expanded stents. The drug coating morphology and elution kinetics were demonstrated to be associated. Significant coating morphological defects were shown to cause deviations in the drug elution profile. [ABSTRACT FROM AUTHOR]

Introduction: First-generation drug-eluting stents (DES) were developed and indeed proved their superiority compared to bare-metal stent in minimizing neo-intimal hyperplasia and in-stent restenosis (ISR), overall, reducing target vessel revascularization (TVR). Newer-generation DES are characterized by thinner struts, more biocompatible and either durable, biodegradable or polymer-free surfaces, better device profile and refined drug elution. Area covered: The EluNIRTM (Medinol, Tel Aviv, Israel) Ridaforolimus Eluting Coronary Stent System is a new DES with unique properties. In this review, we highlight the special characteristics of the stent and summarize relevant clinical data. The EluNIRTM was studied in two clinical trials, the NIREUS trial and the larger, pivotal, BIONICS trial. These trials collectively provide data on the safety, performance, and efficacy of the device. Expert commentary: The newly FDA-approved EluNIRTM stent features an elastomeric durable polymer which elutes a novel drug, Ridaforolimus. The stent has thin struts with variable widths and a delivery catheter with a spring tip. These characteristics may explain the good angiographic and clinical results of this stent, which were noninferior to the FDA-approved Medtronic ResoluteTM stent DES. [ABSTRACT FROM AUTHOR]

Introduction : Event rates after percutaneous coronary interventions (PCI) are higher in small than large coronary vessels but may vary between different drug-eluting stent (DES) types. Aim : To assess the efficacy of two different DES in small vessel disease. Material and methods : Patients with small vessel PCI were randomised 1 : 1 to a first-generation paclitaxel- vs. a second-generation zotarolimus-eluting stent. The primary endpoint was a composite of cardiac death, non-fatal myocardial infarction, and target vessel revascularisation after 2 years. Results: Overall, 191 patients were enrolled: 100 with a paclitaxel- and 91 with a zotarolimus-eluting stent. Baseline characteristics were similar in both groups. After 2 years, rates of the primary endpoint were numerically higher for zotarolimus- than paclitaxel-eluting stents (9.9% vs. 5.0%, hazard ratio 2.09, 95% confidence interval (CI) 0.7–6.2, p = 0.19), which was mainly driven by higher rates of target vessel revascularisation (6.6% vs. 2.0%, hazard ratio 3.39, 95% CI: 0.68–16.78, p = 0.14). Based on this, a total of 1,019 patients would be necessary to demonstrate at least non-inferiority between the DES used. Conclusions : In this pilot study, paclitaxel-eluting stents had a favourable efficacy profile in small vessel disease, although the numbers were too small to draw final conclusions. Based on the prohibitively high sample size for a randomized controlled trial between DES, other treatment options should be considered.

Sarkis Kiramijyan,1 Ming W Liu2 1Division of Cardiology, Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA; 2Heart and Vascular Care Center, White Memorial Medical Center, Los Angeles, CA, USA Abstract: The advent of coronary stents has been a landmark development in the treatment of coronary artery disease with percutaneous coronary intervention. Initial percutaneous treatment using balloon angioplasty alone had limited clinical efficacy due to immediate vascular elastic recoil and dissection, in addition to late negative vascular remodeling and neointimal hyperplasia. With the introduction of coronary stents, initially bare-metal stents (BMS), the problems of dissection and negative remodeling due to injury in addition to vascular elastic recoil were eliminated; however, neointimal hyperplasia remained an ongoing obstacle in the long-term efficacy of stents. Neointimal hyperplasia resulted in in-stent restenosis in 20%–30% of cases after intervention with BMS, which led to high rates of target lesion revascularization. Subsequently, drug-eluting stents (DES) were introduced, which had the added advantage of releasing an anti-proliferative drug from the stent to reduce the neointimal proliferation, thus resulting in the reduction of the rates of in-stent restenosis. Although the first-generation DES had significantly improved outcomes over its predecessor, the BMS, several challenges including stent thrombosis and delayed endothelialization of the stent remained. The second-generation DES have been significantly improved over their first-generation predecessors in regard to efficacy and safety, ie, improved long-term outcomes and significant reductions in stent thrombosis. The duration of dual antiplatelet therapy after DES has also been studied extensively in multiple large trials. A newer generation of stents, including those with bioresorbable polymers, polymer-free, and fully bioresorbable scaffolds is still in the early stages of development. Lastly, the ongoing heated comparison in multiple trials regarding the use of coronary stents vs coronary artery bypass surgery for the treatment of complex/multi-vessel coronary disease continues to evolve. Keywords: bare-metal stent, everolimus, zotarolimus, sirolimus, paclitaxel, percutaneous coronary intervention

Background--Durable polymers used in drug-eluting stents are considered a potential cause of hypersensitivity inflammatory response adversely affecting stent healing. Using a sequential follow-up with optical coherence tomography, we compared the differences in healing profiles of 2 drug-eluting stents with a biodegradable or durable polymer. Methods and Results--Sixty patients with multivessel disease were prospectively enrolled to receive both study stents, which were randomly assigned to 2 individual vessels, a Resolute Integrity zotarolimus-eluting stent with a durable BioLinx polymer and a BioMatrix NeoFlex Biolimus A9-eluting stent with a biodegradable polylactic acid polymer. Optical coherence tomography was performed at baseline, then in 5 randomly assigned monthly groups at 2 to 6 months, and at 9 months in all patients. The primary end point was the difference in optical coherence tomography strut coverage at 9 months. Key secondary end points included angiographic late lumen loss and composite major adverse cardiac events (cardiac death, myocardial infarction, target lesion revascularization, and definite or probable stent thrombosis) at 9 months. Resolute Integrity zotarolimus-eluting stent showed significantly better strut coverage than BioMatrix NeoFlex Biolimus A9-eluting stent at 2 to 6 months (P<0.001) and less variance of percent coverage at 9 months, 99.7% (interquartile range, 99.1-100) versus 99.6% (interquartile range, 96.8-99.9; difference, 0.10; 95% confidence interval, 0.00-1.05; P<0.001). No significant difference was observed in major adverse cardiac events or angiographic end points. Conclusions--Despite having a durable polymer, Resolute Integrity zotarolimus-eluting stent exhibited better strut coverage than BioMatrix NeoFlex Biolimus A9-eluting stent having a biodegradable polymer; both showed similar antiproliferative efficacy. This novel, longitudinal, sequential optical coherence tomography protocol using each patient as own control could achieve conclusive results in small sample size. [ABSTRACT FROM AUTHOR]

Drugeluting metal stents (DESs) have been extensively used in coronary and vascular disease. This type of stents has been proven to provide significantly lower restenosis rates due to the reduction of neo-intimal hyperplasia in comparison to the traditionally used bare metal stents (BMSs). The latter stents have been evaluated for more than a decade in urological practice in an attempt to provide permanent relief of urethral or ureteral obstruction. Although the initial results were promising, long-term experience revealed significant complications, which are mainly attributed to stent-related hyperplastic reaction compromising stent patency. The favorable experience of vascular DESs led to the application of DESs in both the urethra and ureter of animal models. These experimental results demonstrated a reduction of hyperplastic reaction of DESs in comparison to BMSs. Nevertheless, clinical data are currently not available. Considering the fact that DESs are under continuous development, the use of DESs in urology holds promise for the future and seems to be an intriguing field.

Background Although studies have demonstrated comparable efficacy and safety profiles of everolimus- and zotarolimus-eluting stents (EES and ZES, respectively) for a broad spectrum of coronary artery diseases, there is paucity of data concerning their safety and efficacy for coronary chronic total occlusions (CTOs). This study compared the clinical performance of EES and ZES following successful percutaneous coronary intervention for CTOs. Methods The cohort included 539 consecutive CTO patients who underwent successful PCI using EES (n = 313) and ZES (n = 226) between September 2006 and August 2014. The primary outcome was defined as the composite of death, myocardial infarction, and target vessel revascularization. Results During a median follow-up of 3.3 years, in both groups, the primary outcome occurred in 12.2% of patients. After multivariable adjustment, no significant difference was observed between the two groups in the risk of primary outcome [hazard ratio (HR) 1.03, 95% confidence interval (CI) 0.59–1.79, P = 0.930 for ZES compared with EES]. Similarly, there were no significant differences in the risk of death (adjusted HR 0.96, 95% CI 0.43–2.15, P = 925), death or myocardial infarction (adjusted HR 0.93, 95% CI 0.46–1.88, P = 0.829), and target vessel failure (adjusted HR 0.96, 95% CI 0.51–1.82, P = 0.902). The incidence of definite/probable stent thrombosis was relatively low [0% (ZES) vs. 1.0% (EES), P = 0.19]. Conclusion No significant differences were observed between EES and ZES in terms of clinical outcomes for coronary CTOs at 3.3 years. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to explore the safety and efficacy of a dedicated drug-eluting stent for the treatment of coronary lesions with very small reference vessel diameter (RVD). Background Smaller RVD is associated with increased risk for restenosis and target lesion failure (TLF) after stent implantation. Methods This was a prospective, single-arm, multicenter trial of the Resolute Onyx 2.0-mm zotarolimus-eluting stent. The primary endpoint was 12-month TLF, which was compared with a pre-specified performance goal. Subjects with stable or unstable angina or ischemia, target lesions ≤27 mm in length, and RVD ≥2.0 and <2.25 mm were eligible for enrollment. A subset of subjects underwent follow-up angiography at 13 months post-procedure. Results A total of 101 subjects with 104 lesions were enrolled. The mean age was 67.3 ± 9.6 years, 47% of subjects had diabetes, the mean lesion length was 12.6 ± 6.3 mm, and the mean RVD was 1.91 ± 0.26 mm. The rate of TLF at 12 months was 5.0%, fulfilling the pre-specified performance goal of 19% (p < 0.001). The rates of target lesion revascularization and target vessel myocardial infarction were 2.0% and 3.0%, respectively. There were no episodes of stent thrombosis. In-stent late lumen loss was 0.26 ± 0.48 mm, and the rate of binary restenosis was 12.0%. Conclusions In this first report of a drug-eluting stent with a dedicated size to treat lesions with RVD <2.25 mm, the Resolute Onyx 2.0-mm zotarolimus-eluting stent was associated with a low rate of TLF and late lumen loss, without a signal for stent thrombosis. This novel-sized drug-eluting stent appears to be a feasible option for the treatment of coronary lesions in extremely small vessels. (Medtronic Resolute Onyx 2.0 mm Clinical Study; NCT02412501 ) [ABSTRACT FROM AUTHOR]

Purpose: To compare the 1-year outcomes of a durable polymer Zotarolimus-eluting stent (ZES) versus a biodegradable polymer Biolimus-eluting stent (BES) in patients undergoing percutaneous coronary intervention. Materials and Methods: A total of 2083 patients from 2 different registries, 1125 treated with BES in NOBORI registry and 858 received ZES in CONSTANT registry were included in this study. Clinical outcomes were compared with the use of propensity score matching (PSM). The primary endpoint was a composite of major adverse cardiovascular and cerebrovascular events (MACCEs) including cardiac death, myocardial infarction, clinically driven target lesion revascularization and stroke. Secondary end points were individual components of MACCEs as well as the incidence of stent thrombosis at 1-year follow-up. Results: After PSM, 699 matched pairs of patients (n=1398) showed no significant difference between BES and ZES in the risk of composite MACCEs at 1 year (2.6% vs. 1.7%; p=0.36). Cardiac death was not statistically different between groups (0.7% vs. 0.4%, p=0.73). Target lesion revascularization rate was also similar between BES and ZES (1.1% vs. 0.7%, p=0.579). Non-Q wave myocardial infarction, as well as target-vessel revascularization rate, was similar between the two groups (0.14% for BES and 0.72% for ZES). Both stent types were excellent with no cases of stent thrombosis and rate of Q wave myocardial infarction reported during the follow-up period. Conclusion: In this cohort of patients treated with BES or ZES, the rate of MACCEs at 1 year was low and significantly not different between both groups. [ABSTRACT FROM AUTHOR]

Objectives The authors sought to compare the safety and efficacy of the biocompatible durable-polymer zotarolimus-eluting stent with the biodegradable-polymer biolimus-eluting stent in unselected coronary patients. Background Biodegradable-polymer biolimus-eluting stents are superior to first-generation durable-polymer drug-eluting stents in long-term randomized all-comer trials. Long-term data comparing them to second-generation durable-polymer drug-eluting stents are lacking. Methods The study was a randomized, multicenter, all-comer, noninferiority trial in patients with chronic stable coronary artery disease or acute coronary syndromes and at least 1 coronary artery lesion requiring treatment with a drug-eluting stent. Endpoints included major adverse cardiac events (MACE), a composite of safety (cardiac death and myocardial infarction not clearly attributable to a non-target lesion) and efficacy (target lesion revascularization); the individual endpoints of MACE; all-cause mortality; any myocardial infarction; target vessel revascularization; and definite or probable stent thrombosis at 36 months. Results From March 2011 to August 2012, 2,999 patients were randomly assigned (1:1) to receive either the zotarolimus-eluting (1,502 patients) or the biolimus-eluting (1,497 patients) stent. At 3-year follow-up, MACE occurred in 128 (8.6%) patients assigned to the durable-polymer zotarolimus-eluting stent and in 144 (9.6%) assigned to the biodegradable-polymer biolimus-eluting stent (p = 0.36). Occurrence of cardiac death (2.7% vs. 3.4%), myocardial infarction not clearly attributable to a non-target lesion (2.7% vs. 2.5%), and target lesion revascularization (5.4% vs. 5.5%) did not differ significantly between the 2 groups. Definite very late stent thrombosis occurred in 6 (0.4%) patients assigned to the durable-polymer zotarolimus-eluting stent and in 10 (0.7%) assigned to the biodegradable-polymer biolimus-eluting stent (p = 0.33). Conclusions At 3-year follow-up, the durable-polymer zotarolimus-eluting stent and the biodegradable-polymer biolimus-eluting stent were similar in clinical outcome, with no significant difference in safety and efficacy outcomes, including stent thrombosis. [ABSTRACT FROM AUTHOR]

Aims At present no proven standard treatment for drug-eluting stent (DES) restenosis is available, and the efficacy and safety of everolimus-eluting stent (EES) and zotarolimus-eluting stent (ZES) for DES restenosis are limited. The purpose of this prospective, randomized 9-month intracoronary ultrasound (IVUS) and 3-year clinical follow-up study was to compare the effects of EESs and ZESs on neointima volume and major adverse cardiovascular events (MACEs) such as death, myocardial infarction (MI), target lesion revascularization (TLR) and stent thrombosis in DES restenosis patients.Methods and results Patients were eligible for this study if they were between 40 and 75 years old with in-stent restenosis >50% by quantitative coronary angiographic analysis in DES or within 5 mm of the stent edges with signs of ischaemia. Eligible patients (n = 304, 146 women and 158 men) were randomly assigned to receive either EES (158 patients) or ZES (146 patients). The primary endpoint of the study was to compare neointima volume between the EES and ZES groups at the 9-month follow-up IVUS. MACEs, including death, non-fatal MI, stent thrombosis and the need for repeated TLR within 3 years, were noted. The 9-month angiographic and IVUS follow-up showed no significant differences in late lumen loss (0.40 ± 0.56 vs. 0.45 ± 0.61 mm, P = 0.57, respectively) and neointima volume (0.51 ± 0.48 vs. 0.56 ± 0.54 mm3/1 mm, P = 0.47, respectively) in the EES and the ZES groups. Composite MACEs such as death, MI, stent thrombosis and TLR during 3-year follow-up were comparable between the two groups [15.8% (n = 25) in the EES group and 22.6% (n = 33) in the ZES group, P = 0.276], independent of de novo DES type, sex, age, body mass index, presence of diabetes, hypertension and dyslipidaemia.Conclusions Patients with first- and second-generation DES restenosis, both EES and ZES implantation were effective and safe in reducing neointima volume and late loss with a comparable rate of MACEs independent of cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Introduction: Event rates after percutaneous coronary interventions (PCI) are higher in small than large coronary vessels but may vary between different drug-eluting stent (DES) types. Aim: To assess the efficacy of two different DES in small vessel disease. Material and methods: Patients with small vessel PCI were randomised 1 : 1 to a first-generation paclitaxel- vs. a second-generation zotarolimus-eluting stent. The primary endpoint was a composite of cardiac death, non-fatal myocardial infarction, and target vessel revascularisation after 2 years. Results: Overall, 191 patients were enrolled: 100 with a paclitaxel- and 91 with a zotarolimus-eluting stent. Baseline characteristics were similar in both groups. After 2 years, rates of the primary endpoint were numerically higher for zotarolimus- than paclitaxel- eluting stents (9.9% vs. 5.0%, hazard ratio 2.09, 95% confidence interval (CI) 0.7–6.2, p = 0.19), which was mainly driven by higher rates of target vessel revascularisation (6.6% vs. 2.0%, hazard ratio 3.39, 95% CI: 0.68–16.78, p = 0.14). Based on this, a total of 1,019 patients would be necessary to demonstrate at least non-inferiority between the DES used. Conclusions: In this pilot study, paclitaxel-eluting stents had a favourable efficacy profile in small vessel disease, although the numbers were too small to draw final conclusions. Based on the prohibitively high sample size for a randomized controlled trial between DES, other treatment options should be considered. [ABSTRACT FROM AUTHOR]

Background: Improved outcomes in patients with diabetes mellitus undergoing percutaneous coronary intervention remain an unmet clinical need. We assessed the long-term efficacy and safety of novel polymer-free sirolimus- and probucol-eluting stent in diabetic patients enrolled in intracoronary stenting and angiographic results: test efficacy of sirolimus- and probucol-eluting versus zotarolimus-eluting stents 5 trial. Methods: In a pre-specified subgroup analysis, outcomes of diabetic patients treated with a sirolimus- and probucol-eluting stent or a second-generation zotarolimus-eluting stent were compared. The primary endpoint was a device-oriented composite outcome comprising cardiac death, target vessel-related myocardial infarction (MI), or target lesion revascularization (TLR) at 5-year follow-up. Event-free survival was assessed using the Kaplan-Meier method. Hazard ratios (HR) and 95 % confidence intervals (CI) were estimated from univariate Cox proportional hazards models. Results: A total of 870 patients with diabetes mellitus were treated with either a sirolimus- and probucol-eluting stent (n = 575) or a second-generation zotarolimus-eluting stent (n = 295). At 5 years, the rate of device-oriented composite endpoint was comparable between the sirolimus- and probucol-eluting stent and the second-generation zotarolimus-eluting stent (32.9 versus 33.4 %, HR 0.88, 95 % CI 0.76-1.26). No significant differences were observed between the sirolimus- and probucol-eluting stent and the second-generation zotarolimus-eluting stent groups in the incidence of cardiac death (15.6 versus 16.7 % HR 0.92, 95 % CI 0.63-1.32), target-vessel MI (4.6 versus 6.6 %, HR 0.73, 95 % CI 0.40-1.34), and TLR (18.6 versus 18.8 %, HR 1.00, 95 % CI, 0.72-1.41). The rate of definite or probable stent thrombosis was low and similar in both groups (2.5 versus 2.6 %, HR 1.02, 95 % CI, 0.41-2.52). Conclusions: In patients with diabetes the long-term efficacy and safety of a polymer-free sirolimus- and probucol-eluting stent were comparable to a second-generation durable polymer zotarolimus-eluting stent. [ABSTRACT FROM AUTHOR]

Background: In percutaneous coronary intervention (PCI) patients new-generation drug-eluting stent (DES) has reduced adverse events in comparison to early-generation DES. The aim of the current study was to investigate the long-term clinical efficacy and safety of new-generation DES versus early-generation DES for PCI of unprotected left main coronary artery (uLMCA) disease. Methods: The patient-level data from the ISAR-LEFT MAIN and ISAR-LEFT MAIN 2 randomized trials were pooled. The clinical outcomes of PCI patients assigned to new-generation DES (everolimus- or zotarolimus-eluting stent) versus early-generation DES (paclitaxel- or sirolimus-eluting stent) were studied. The primary endpoint was the composite of death, myocardial infarction (MI), target lesion revascularization and stroke (MACCE, major adverse cardiac and cerebrovascular event). Results: In total, 1257 patients were available. At 3 years, the risk of MACCE was comparable between patients assigned to new-generation DES or early-generation DES (28.2 versus 27.5 %, hazard ratio-HR 1.03, 95 % confidence intervals-CI 0.83-1.26; P = 0.86). Definite/probable stent thrombosis was low and comparable between new-generation DES and early-generation DES (0.8 versus 1.6 %, HR 0.52, 95 % CI 0.18-1.57; P = 0.25); in patients treated with new-generation DES no cases occurred beyond 30 days. Diabetes increased the risk of MACCE in patients treated with new-generation DES but not with early-generation DES ( P = 0.004). Conclusions: At 3-year follow-up, a PCI with new-generation DES for uLMCA disease shows comparable efficacy to early-generation DES. Rates of stent thrombosis were low in both groups. Diabetes significantly impacts the risk of MACCE at 3 years in patients treated with new-generation DES for uLMCA disease. ClinicalTrials.gov Identifiers: NCT00133237; NCT00598637. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to evaluate the late clinical performance of a polymer-free sirolimus- and probucol-eluting stent compared with a new-generation durable polymer-based zotarolimus-eluting stent. Background It was previously shown that polymer-free sirolimus- and probucol-eluting stents were noninferior to zotarolimus-eluting stents at 12 months. However, long-term follow-up of these devices is critical to evaluate late comparative efficacy. Methods In a clinical trial with minimal exclusion criteria, 3,002 patients were randomly assigned to treatment with polymer-free sirolimus- and probucol-eluting stents versus zotarolimus-eluting stents. The primary endpoint was the combined incidence of cardiac death, target vessel–related myocardial infarction, or target lesion revascularization. Results At 5 years, there was no difference in the incidence of the primary endpoint between sirolimus- and probucol-eluting stents and zotarolimus-eluting stents (23.8% vs. 24.2%, respectively; hazard ratio: 0.98; 95% confidence interval: 0.84 to 1.15; p = 0.80). The rates of the individual components of the primary endpoint were also comparable in both groups. The incidence of definite or probable stent thrombosis was low in both groups (1.3% vs. 1.6%, respectively; hazard ratio: 0.86; 95% confidence interval: 0.46 to 1.62; p = 0.64). The rates of any death, myocardial infarction, and revascularization were similar in both groups. Results were consistent across pre-specified subgroups of age, sex, diabetes, and vessel size. Conclusions Long-term outcomes of patients treated with polymer-free sirolimus- and probucol-eluting stents compared with a new-generation durable polymer-based zotarolimus-eluting stent were similar. Rates of stent thrombosis were low and comparable in both treatment groups, with few events beyond 12 months. (Efficacy Study of Rapamycin- vs. Zotarolimus-Eluting Stents to Reduce Coronary Restenosis [ISAR-TEST-5]; NCT00598533 ) [ABSTRACT FROM AUTHOR]

Background: The efficacy of second-generation drug-eluting stents (DES) in treating in-stent restenosis (ISR) compared to first-generation DES and non-DES treatment methods in real-world cohorts has not yet been adequately addressed. This research intends to examine optimum treatment of in-stent restenosis, considering first-generation DES, second-generation DES and non-DES treatment methods in a real-world cohort.Methods: Retrospective analysis was performed on 114 patients treated for native-vessel BMS or DES ISR. Thirty-two were treated with a first-generation DES (81% sirolimus, 19% paclitaxel), 32 with a second-generation DES (72% everolimus, 28% zotarolimus) and 28 with non-DES methods (32% bare-metal stent, 39% balloon angioplasty, 29% cutting balloon). The composite primary endpoint was total adverse cardiac events, recurrent stable angina, unstable angina, myocardial infarction (MI), target vessel revascularisation (TVR) and cardiac death at minimum clinical follow-up of six months.Results: Primary endpoint rates were significantly higher in the non-DES and second-generation DES treatment groups than in first-generation DES (42.9%, 25.9%, 6.2%; p=0.004). Rates of MI and TVR were significantly higher in the non-DES treatment group, compared to first and second-generation DES (MI: 17.9%, 0%, 5.6%; p=0.018; TLR: 21.4%, 3.1%, 7.4%; p=0.041).Conclusions: First-generation DES may be superior to second-generation DES and non-DES in treating BMS or DES ISR with regard to overall adverse cardiac events. [ABSTRACT FROM AUTHOR]

Background: Late and very late stent thrombosis after drug-eluting stent implantation is a major concern. The present study evaluated difference in the effects of sirolimus, paclitaxel and zotarolimus on endothelial cells.Methods: Mouse endothelial cells were seeded in a 6-well plate. Cells were cultured with an antiproliferative drug at the expected concentrations for each well for 24 hours before making 3 scratch lines with a pipette tip. After a 4.5 hour incubation period, 3 reference scratch lines, vertically across the original scratch lines, were made in the same way. The experiment was repeated at least 6 times (6 plates). Measurements were performed at 9 crossings of each well. Wound healing ratio was calculated as 1-(distance of the first scratch/distance of the second scratch). % cell migration was calculated as (wound healing ratio at an expected drug concentration/wound healing ratio with no drug) × 100. Average % cell migration at 54 crossings of 6 plates was calculated.Results: Paclitaxel inhibited cell migration in a concentration-dependent manner. On the other hand, concentration-dependent inhibition was not observed for sirolimus or zotarolimus. Sirolimus showed a stronger inhibitory effect on migration of endothelial cells compared to zotarolimus.Conclusions: The difference in the effect of antiproliferative drugs of drug-eluting stents on endothelial cells may be associated with relatively faster re-endothelialization of zotarolimus-eluting stent compared to the 1st generation DES. [ABSTRACT FROM AUTHOR]

Background--Newer-generation drug-eluting stents that release zotarolimus or everolimus have been shown to be superior to the first-generation drug-eluting stents. However, data comparing long-term safety and efficacy of zotarolimus- (ZES) and everolimus-eluting stents (EES) are limited. RESOLUTE all-comers (Randomized Comparison of a Zotarolimus- Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention) trial compared these 2 stents and has shown that ZES was noninferior to EES at 12-month for the primary end point of target lesion failure. We report the secondary clinical outcomes at the final 5-year follow-up of this trial. Methods and Results--RESOLUTE all-comer clinical study is a prospective, multicentre, randomized, 2-arm, open-label, noninferiority trial with minimal exclusion criteria. Patients (n=2292) were randomly assigned to treatment with either ZES (n=1140) or EES (n=1152). Patient-oriented composite end point (combination of all-cause mortality, myocardial infarction, and any revascularizations), device-oriented composite end point (combination of cardiac death, target vessel myocardial infarction, and clinically indicated target lesion revascularization), and major adverse cardiac events (combination of all-cause death, all myocardial infarction, emergent coronary bypass surgery, or clinically indicated target lesion revascularization) were analyzed at 5-year follow-up. The 2 groups were well-matched at baseline. Fiveyear follow-up data were available for 98% patients. There were no differences in patient-oriented composite end point (ZES 35.3% versus EES 32.0%, P=0.11), device-oriented composite end point (ZES 17.0% versus EES 16.2%, P=0.61), major adverse cardiac events (ZES 21.9% versus EES 21.6%, P=0.88), and definite/probable stent thrombosis (ZES 2.8% versus EES 1.8%, P=0.12). Conclusions--At 5-year follow-up, ZES and EES had similar efficacy and safety in a population of patients who had minimal exclusion criteria. [ABSTRACT FROM AUTHOR]

Aims To compare the long-term clinical safety between two drug-eluting stents with different healing characteristics in the Patient Related Outcomes with Endeavour (E-ZES) vs. Cypher (C-SES) Stenting Trial (PROTECT). At 3 years, there was no difference in the primary outcome of definite or probable stent thrombosis or in the other main secondary clinical outcomes consisting of the composite of death or myocardial infarction (MI). Prespecified 4-year clinical follow-up was analysed. Methods and results Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial was a prospective, open-label randomized-controlled superiority trial powered to look at differences in long-term clinical safety, including stent thrombosis. Dual antiplatelet therapy (DAPT) was prescribed for ≥3 months and up to 12 months based on current guidelines. Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial enrolled 8791 patients undergoing elective or emergency PCI to E-ZES or C-SES. There was no difference in DAPT usage between the two groups up to 4 years. At 4-year follow-up, the primary outcome occurred in 1.6% of E-ZES vs. 2.6% of C-SES patients [HR 0.63 (95% CI 0.46–0.85), P = 0.003]. The composite of all-cause death or large MI occurred in 6.7% of E-ZES vs. 8.0% of C-SES-treated patients [HR 0.84 (95% CI 0.71–0.98), P = 0.024]. Conclusions Drug-eluting coronary stents with different healing characteristics demonstrated different late safety profiles: after 4 years, compared with C-SES, E-ZES reduced the risk of stent thrombosis and the risk of the composite endpoints of death or MI. Appropriately powered large-scale trials with long-term follow-up are critical to determine clinical safety and efficacy of permanently implanted coronary stents. [ABSTRACT FROM PUBLISHER]

There have been attempts to find new approaches to the treatment of multivessel coronary artery disease without increasing adverse events. Deployment of drug-eluting stents (DES) for complex lesions and bare-metal stents (BMS) for simpler lesions, although already in wide use, has not been well supported by clinical study. A cohort of 1,658 patients who underwent multivessel percutaneous coronary intervention from March 2003 through June 2011 was studied for 1 year. These patients were divided into 3 groups: BMS only (599 patients); DES only (481 patients); and hybrid stent-ing (578 patients). Baseline characteristics were similar except for hyperlipidemia and moderate-to-severe mitral regurgitation, which were more frequent in the DES and hybrid groups, respectively. Lesion characteristics were more complex in the DES group, compared with the other groups: more B2/C type lesions, longer stents, and smaller reference-vessel diameters (P <0.001). The rates of major adverse cardiac events (MACE) at 1 year were similar between the groups (BMS=5.2%, hybrid=3.9%, and DES=3.4%; P=0.248). Subgroup analysis yielded no differences in death, nonfatal myocardial infarction, target-vessel revascularization, or target-lesion revascularization. On multivariable analysis, the strongest predictors of 1-year MACE were percutaneous intervention complicated by dissection, renal failure, left ventricular ejection fraction below 0.40, mean lesion length, reference vessel diameter, and percutaneous intervention on the left circumflex coronary artery. The latter two had inverse relationships with MACE. In conclusion, implanting the DES for more complex lesions and the BMS for simpler lesions seems more sensible than the exclusive use of the DES or the BMS. [ABSTRACT FROM AUTHOR]

Aim To investigate the putative modifying effect of dual antiplatelet therapy (DAPT) use on the incidence of stent thrombosis at 3 years in patients randomized to Endeavor zotarolimus-eluting stent (E-ZES) or Cypher sirolimus-eluting stent (C-SES). Methods and results Of 8709 patients in PROTECT, 4357 were randomized to E-ZES and 4352 to C-SES. Aspirin was to be given indefinitely, and clopidogrel/ticlopidine for ≥3 months or up to 12 months after implantation. Main outcome measures were definite or probable stent thrombosis at 3 years. Multivariable Cox regression analysis was applied, with stent type, DAPT, and their interaction as the main outcome determinants. Dual antiplatelet therapy adherence remained the same in the E-ZES and C-SES groups (79.6% at 1 year, 32.8% at 2 years, and 21.6% at 3 years). We observed a statistically significant (P = 0.0052) heterogeneity in treatment effect of stent type in relation to DAPT. In the absence of DAPT, stent thrombosis was lower with E-ZES vs. C-SES (adjusted hazard ratio 0.38, 95% confidence interval 0.19, 0.75; P = 0.0056). In the presence of DAPT, no difference was found (1.18; 0.79, 1.77; P = 0.43). Conclusion A strong interaction was observed between drug-eluting stent type and DAPT use, most likely prompted by the vascular healing response induced by the implanted DES system. These results suggest that the incidence of stent thrombosis in DES trials should not be evaluated independently of DAPT use, and the optimal duration of DAPT will likely depend upon stent type (Clinicaltrials.gov number NCT00476957). [ABSTRACT FROM PUBLISHER]

Optical coherence tomography (OCT) images and histology images of metal stents (MSs) inserted in animal ureters were compared, and the reliability of an OCT-based automated method for the performance of quantitative evaluation of ureteral MSs was evaluated. A zotarolimus-eluting metal stent (ZES) and a bare metal stent (BMS) were inserted in each ureter of ten pigs and six rabbits. OCT was performed in unobstructed stented ureters. Histopathologic examination of the stented ureters embedded in glycol-methacrylate took place. Quadrants of OCT images were compared to their respective histologic images by employing two independent observers who delineated different layers in the quadrants of OCT images and correlated them to the respective histologic quadrants. Manual (integrated OCT device software) and automated measurements of the OCT images using an automated strut detection method were compared. The observers highly agreed on the delineation of urothelium from the lamina propria and the lamina propria from the muscle layer of the ureteral wall. The algorithm measurements were similar to the manual measurements, and the algorithm proved to be reliable in the evaluation of ureteral MSs. Significantly higher endothelial hyperplasia of the BMSs in comparison to the ZESs was also quantitatively demonstrated by the strut detection method. OCT proved to be a reliable method for the evaluation of ureteral MSs. OCT provided images of the stented ureteral lumen similar to light microscopy quality. Measurements of the stented ureter are reliably performed by the automated strut detection method. [ABSTRACT FROM AUTHOR]

Abstract: Background: Currently one of the major problems that interventional pulmonologists have to face is the increased proliferation of fibrinous tissue on the site of the stent placement, and usually at the two ends. Materials and methods: The drugs rapamycin and pirfenidone were chosen for our experiment. Fibroblasts were also cultured in order to administer pirfenidone and rapamycin in different concentrations. The following cell viability methods were used: (a) Senescence – Cell Titer Assay, (b) Necrosis – Cyto Tox Assay and (c) Apoptosis – Caspase-Glo 3/7 Assay. Results: Rapamycin has minimal to no effect on fibroblasts regarding apoptosis, senescence and necrosis. 0.1 to 1?M. Pirfenidone concentrations lead to an elevated cell metabolism because cells try to evade the cytotoxic effect of the drug. Increasing Pirfenidone concentrations lead to higher apoptosis rates. 10?M pirfenidone induces the highest apoptosis rates in this experiment and reduce cell viability to a minimum. Conclusion: Necrosis is unaffected by the investigated drugs. [Copyright &y& Elsevier]

Objectives: This study sought to compare everolimus-eluting stents (EES) versus Resolute zotarolimus-eluting stents (ZES) in terms of patient- or stent-related clinical outcomes in an “all-comer” group of patients with diabetes mellitus (DM) who underwent percutaneous coronary intervention. Background: DM significantly increases the risk of adverse events after percutaneous coronary intervention. The efficacy and safety of second-generation drug-eluting stents, in particular EES versus ZES, in patients with DM have not been extensively evaluated. Methods: Patients with DM (1,855 of 5,054 patients, 36.7%) from 2 prospective registries (the EXCELLENT [Efficacy of Xience/Promus Versus Cypher in Reducing Late Loss After Stenting] registry and RESOLUTE-Korea [Registry to Evaluate the Efficacy of Zotarolimus-Eluting Stent]) who were treated with EES (n = 1,149) or ZES (n = 706) were compared. Stent-related outcome was target lesion failure (TLF), and patient-oriented composite events were a composite of all-cause mortality, any myocardial infarction, and any revascularization. Results: Despite a higher risk patient profile in the ZES group, both TLF (43 of 1,149 [3.7%] vs. 25 of 706 [3.5%], p = 0.899) and patient-oriented composite events (104 of 1,149 [9.1%] vs. 72 of 706 [10.2%], p = 0.416) were similar between the EES and ZES in patients with DM at 1 year. In those without DM, EES and ZES also showed comparable incidence of TLF (39 of 1,882 [2.1%] vs. 33 of 1,292 [2.6%], p = 0.370) and patient-oriented composite events (119 of 1,882 [6.3%] vs. 81 of 1,292 [6.3%], p = 0.951), which were all significantly lower than in the DM patients. These results were corroborated by similar findings from the propensity score-matched cohort. Upon multivariate analysis, chronic renal failure was the most powerful predictor of TLF in DM patients (hazard ratio: 4.39, 95% confidence interval: 1.91 to 10.09, p < 0.001). Conclusions: After unrestricted use of second-generation drug-eluting stents in all-comers receiving percutaneous coronary intervention, both EES and ZES showed comparable clinical outcomes in the patients with DM up to 1 year of follow-up. DM compared with non-DM patients showed significantly worse patient- and stent-related outcomes. Nonetheless, overall incidences of TLF were low, even in the patients with DM, suggesting excellent safety and efficacy of both types of second-generation drug-eluting stents in this high-risk subgroup of patients. [Copyright &y& Elsevier]

Drug eluting stents were an important addition to the interventional options available for patients with coronary artery disease, and they effectively reduced the risk of restenosis observed with bare metal stents. However, the drugs and polymers used in the composition of drug eluting stents were found to delay vascular healing and elicit inflammatory responses, which contributed to late and very late stent thrombosis events. Newer generation drug eluting stents have been engineered with polymers that are more biocompatible and have more favorable drug elution profiles. The Resolute® zotarolimus eluting stent (R-ZES) is a new-generation drug eluting stent. The Global RESOLUTE clinical program was designed to evaluate the safety and efficacy of the R-ZES. The studies conducted under this program have established that the R-ZES safely and effectively treats coronary artery stenosis, with low rates of target lesion failure, target vessel revascularization, and stent thrombosis during extended follow-up. [ABSTRACT FROM AUTHOR]

Drugeluting metal stents (DESs) have been extensively used in coronary and vascular disease. This type of stents has been proven to provide significantly lower restenosis rates due to the reduction of neo-intimal hyperplasia in comparison to the traditionally used bare metal stents (BMSs). The latter stents have been evaluated for more than a decade in urological practice in an attempt to provide permanent relief of urethral or ureteral obstruction. Although the initial results were promising, long-term experience revealed significant complications, which are mainly attributed to stent-related hyperplastic reaction compromising stent patency. The favorable experience of vascular DESs led to the application of DESs in both the urethra and ureter of animal models. These experimental results demonstrated a reduction of hyperplastic reaction of DESs in comparison to BMSs. Nevertheless, clinical data are currently not available. Considering the fact that DESs are under continuous development, the use of DESs in urology holds promise for the future and seems to be an intriguing field. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to compare the safety and efficacy of the zotarolimus-eluting stent (ZES) and the everolimus-eluting stent (EES) for treatment of unprotected left main coronary artery (uLMCA) disease. Background: The second-generation ZES and EES have reduced the risk of restenosis in large patient cohorts. However, their comparative performance in uLMCA lesions is not known. Methods: In this study, patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention for uLMCA lesions were randomly assigned to receive either a ZES (n = 324) or an EES (n = 326). The primary endpoint was the combined incidence of death, myocardial infarction, and target lesion revascularization at 1 year. Secondary endpoints were definite or probable stent thrombosis at 1 year and angiographic restenosis based on analysis of the left main coronary artery area at follow-up angiography. Results: At 1 year, the cumulative incidence of the primary endpoint was 17.5% in the ZES group and 14.3% in the EES group (relative risk: 1.26; 95% confidence interval [CI]: 0.85 to 1.85; p = 0.25). Three patients in the ZES group (0.9%) and 2 patients in the EES group (0.6%) experienced definite or probable stent thrombosis (p > 0.99). All-cause mortality at 1 year was equal in the 2 groups (5.6%; relative risk: 1.00; 95% CI: 0.52 to 1.93; p = 0.98). Angiographic restenosis occurred in 21.5% of patients in the ZES group and 16.8% in the EES group (relative risk: 1.28; 95% CI: 0.86 to 1.92; p = 0.24). Conclusions: Within the statistical limitations of the present study, treatment of uLMCA lesions with a ZES or an EES provided comparable clinical and angiographic outcomes at 1-year follow-up. (Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for Unprotected Coronary Left Main Lesions [ISAR-LEFT MAIN-2]; NCT00598637) [Copyright &y& Elsevier]

The efficacy and safety of drug-eluting stents (DES) in patients with ST-segment-elevation myocardial infarction (STEMI) is controversial. Consequently, DES implantation has a class IIa indication in the American College of Cardiology/American Heart Association and the European Society of Cardiology STEMI guidelines.PUBMED, EMBASE, and CENTRAL were searched for randomized clinical trials, until March 2013, comparing any of the 5 Food and Drug Administration-approved durable stent and polymer DES (sirolimus eluting stent, paclitaxel eluting stent, everolimus-eluting stent [EES], zotarolimus-eluting stent, and zotarolimus-eluting stent resolute), against each other or bare metal stents (BMS), and enrolling ≥50 patients with STEMI. Efficacy (target vessel revascularization) and safety (death, myocardial infarction, and stent thrombosis) outcomes at the longest reported follow-up times were evaluated. Twenty-eight randomized clinical trials with 34 068 patient-years of follow-up on subjects with STEMI fulfilled the inclusion criteria. When compared with BMS (reference rate ratio [RR] of 1), sirolimus eluting stent (RR, 0.46; 95% credibility interval [CrI], 0.36-0.56), paclitaxel eluting stent (RR, 0.69; 95% CrI, 0.53-0.87), and EES (RR, 0.42; 95% CrI, 0.26-0.62) were associated with a statistically significant reduction in rate of target vessel revascularization, with the point estimate for zotarolimus-eluting stent resolute trending in a similar direction. There was no increase in the risk of death, myocardial infarction, or stent thrombosis with any DES compared with BMS. Moreover, EES was associated with a statistically significant reduction in the rate of stent thrombosis when compared with sirolimus eluting stent (RR, 0.38; 95% CrI, 0.21-0.74), paclitaxel eluting stent (RR, 0.39; 95% CrI, 0.21-0.73), and even BMS (RR, 0.42; 95% CrI, 0.23-0.76). There was a 74% probability that EES had the lowest rate of any stent thrombosis when compared with all other stent types (no data on zotarolimus-eluting stent resolute). There was no increase in very late stent thrombosis with EES versus BMS (RR, 0.89; 95% CrI, 0.09-8.67).In patients with STEMI, DES versus BMS was associated with substantial decrease in the risk of target vessel revascularization without compromising safety. EES had the added advantage of substantial reduction in the risk of stent thrombosis when compared with first-generation DES and BMS with no increase in very late stent thrombosis. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to compare the long-term effects of drug-eluting stent (DES) compared with bare-metal stent (BMS) implantation in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. Background: The randomized DEDICATION (Drug Elution and Distal Protection in Acute Myocardial Infarction) trial evaluated the outcome after DES compared with BMS implantation in patients with STEMI undergoing primary percutaneous coronary intervention. Methods: Patients with a high-grade stenosis/occlusion of a native coronary artery presenting with symptoms <12 h and ST-segment elevation were enrolled after giving informed consent. Patients were randomly assigned to receive a DES or a BMS in the infarct-related lesion. Patients were followed for at least 5 years, and clinical endpoints were evaluated from population registries and hospital charts. The main endpoint was the occurrence of the first major adverse cardiac event (MACE), defined as cardiac death, nonfatal recurrent myocardial infarction, and target lesion revascularization. Results: Complete clinical status was available in 623 patients (99.5%) at 5 years follow-up. The combined MACE rate was insignificantly lower in the DES group (16.9% vs. 23%), mainly driven by a lower need of repeat revascularization (p = 0.07). Whereas the number of deaths from all causes tended to be higher in the DES group (16.3% vs. 12.1%, p = 0.17), cardiac mortality was significantly higher (7.7% vs. 3.2%, p = 0.02). The 5-year stent thrombosis rates were generally low and similar between the DES and the BMS groups. No cardiac deaths occurring within 1 month could be clearly ascribed to stent thrombosis, whereas stent thrombosis was involved in 78% of later-occurring deaths. Conclusions: The 5-year MACE rate was insignificantly different, but the cardiac mortality was higher after DES versus BMS implantation in patients with STEMI. Stent thrombosis was the main cause of late cardiac deaths. [Copyright &y& Elsevier]

Background-Drug-coated balloons are increasingly used for peripheral vascular disease, and, yet, mechanisms of tissue uptake and retention remain poorly characterized. Most systems to date have used paclitaxel, touting its propensity to associate with various excipients that can optimize its transfer and retention. We examined zotarolimus pharmacokinetics. Methods and Results-Animal studies, bench-top experiments, and computational modeling were integrated to quantify arterial distribution after zotarolimus-coated balloon use. Drug diffusivity and binding parameters for use in computational modeling were estimated from the kinetics of zotarolimus uptake into excised porcine femoral artery specimens immersed in radiolabeled drug solutions. Like paclitaxel, zotarolimus exhibited high partitioning into the arterial wall. Exposure of intimal tissue to drug revealed differential distribution patterns, with zotarolimus concentration decreasing with transmural depth as opposed to the multiple peaks displayed by paclitaxel. Drug release kinetics was measured by inflating zotarolimus-coated balloons in whole blood. In vivo drug uptake in swine arteries increased with inflation time but not with balloon size. Simulations coupling transmural diffusion and reversible binding to tissue proteins predicted arterial distribution that correlated with in vivo uptake. Diffusion governed drug distribution soon after balloon expansion, but binding determined drug retention. Conclusions-A large bolus of zotarolimus releases during balloon inflation, some of which pervades the tissue, and a fraction of the remaining drug adheres to the tissue-lumen interface. As a result, the duration of delivery modulates tissue uptake where diffusion and reversible binding to tissue proteins determine drug transport and retention, respectively. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate late safety and efficacy outcomes among patients enrolled in clinical trials comparing Endeavor zotarolimus-eluting stents (E-ZES) (Medtronic, Inc., Santa Rosa, California) with first-generation drug-eluting stents (DES) and bare-metal stents (BMS). Background: Despite demonstration of higher angiographic luminal loss and restenosis with E-ZES compared with alternative DES, whether differences in these early angiographic measures translate into more disparate late clinical events is uncertain. Methods: Among 3,616 patients undergoing percutaneous coronary revascularization in 5 registration trials, late safety and efficacy events were compared between E-ZES (n = 2,132) versus sirolimus- or paclitaxel-eluting stents (n = 888) or BMS (n = 596). Results: Compared with a parallel cohort of patients treated with first-generation DES and BMS, 5-year rates of cardiac death/myocardial infarction (MI) (5.8% vs. 8.8% DES, p = 0.003; vs. 8.4% BMS, p = 0.02) and major adverse cardiac events (16.1% vs. 20.6% DES, p = 0.009; vs. 24.6% BMS, p < 0.001) were significantly lower with E-ZES. The E-ZES was associated with significantly lower target lesion revascularization (TLR) compared with BMS (7.4% vs. 16.3%, p < 0.001) but similar to comparator DES (7.4% vs. 8.1%, p = 0.63). Despite higher TLR in the first year with E-ZES compared with DES, between 1- and 5-year follow-up, rates of cardiac death/MI, TLR, and definite/probable stent thrombosis were significantly lower with E-ZES. Conclusions: Over 5 years, significant differences in cardiac death/MI and composite endpoints favored treatment with E-ZES over comparator BMS and DES. Rates of clinical restenosis and safety events, including stent thrombosis beyond the first year of revascularization, remain stable with E-ZES, leading to significant differences compared with first-generation DES. [ABSTRACT FROM AUTHOR]

The need to develop a local antirestenotic mechanism to prevent in-stent thrombosis has driven the development of new generation stents. The Resolute Integrity® stent is a zotarolimus-eluting system with a new BioLinx™ polymer that allows a slower drug elution. Recently available data has shown the clinical efficacy and safety of this stent in randomized and observational studies. The Resolute Integrity stent system has demonstrated noninferiority when compared with other stents and holds the promise to treat more complex coronary lesions. [ABSTRACT FROM AUTHOR]

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Objectives: This study sought to examine the 3-year clinical outcomes in patients treated with the Endeavor (Medtronic, Santa Rosa, California) zotarolimus-eluting stent (ZES) or the Cypher (Cordis, Johnson & Johnson, Warren, New Jersey) sirolimus-eluting stent (SES) in routine clinical practice. Background: The long-term clinical outcome in patients treated with ZES in comparison with SES is unclear. Methods: The authors randomized 2,332 patients to ZES (n = 1,162) or SES (n = 1,170) implantation. Endpoints included major adverse cardiac events (MACE), a composite of cardiac death, myocardial infarction, or target vessel revascularization; the individual endpoints of MACE; and definite stent thrombosis. Results: At 3-year follow-up, the MACE rate was higher in patients treated with ZES than in patients treated with SES (148 [12.9%] vs. 116 [10.1%]; hazard ratio [HR]: 1.33, 95% confidence interval [CI]: 1.04 to 1.69; p = 0.022). Target vessel revascularization was more frequent in the ZES group compared with the SES group (103 [9.1%] vs. 76 [6.7%]; HR: 1.40, 95% CI: 1.04 to 1.89; p = 0.025), whereas the occurrence of myocardial infarction (3.8% vs. 3.3%) and cardiac death (2.8% vs. 2.8%) did not differ significantly. Although the rate of definite stent thrombosis was similar at 3-year follow-up (1.1% vs. 1.4%), very late (12 to 36 months) definite stent thrombosis occurred in 0 (0%) patients in the ZES group versus 12 (1.1%) patients in the SES group (p = 0.0005). Conclusions: Although the 3-year MACE rate is higher in patients treated with ZES versus SES, our data highlight a late safety problem concerning definite stent thrombosis with the use of SES. This finding underscores the importance of long-term follow-up in head-to-head comparisons of drug-eluting stents. (Randomized Clinical Comparison of the Endeavor and the Cypher Coronary Stents in Non-selected Angina Pectoris Patients [SORT OUT III]; NCT00660478) [ABSTRACT FROM AUTHOR]

A prompt reperfusion with primary percutaneous coronary intervention represents the current gold standard treatment for patients with acute myocardial infarction. In this setting, coronary stents have been shown to improve outcomes compared to plain angioplasty and are routinely used. However, the stent selection among patients with acute myocardial infarction is still a matter of some debate. An increased risk of very late (>1-year) stent thrombosis has been associated with the use of early-generation drug-eluting stents (DES), leading to concerns regarding the long-term safety of these devices. Newer-generation DES were developed with the aim of addressing this safety issue, and were recently investigated in a few randomized studies in patients with acute myocardial infarction. The objective of the present review is to summarize the accumulated evidence, to guide the stent selection in patients with acute myocardial infarction. [ABSTRACT FROM AUTHOR]

Background--Drug-eluting stents (DES) have been in clinical use for nearly a decade; however, the relative short- and long-term efficacy and safety of DES compared with bare-metal stents (BMS) and among the DES types are less well defined. Methods and Results--PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials, until March 2012, that compared any of the Food and Drug Administration-approved durable stent and polymer DES (sirolimus-eluting stent [SES], paclitaxel-eluting stent [PES], everolimus-eluting stent [EES], zotarolimus-eluting stent [ZES], and ZES-Resolute [ZES-R]) with each other or against BMS for de novo coronary lesions, enrolling at least 100 patients and with follow-up of at least 6 months. Short-term (<1 year) and long-term efficacy (target-vessel revascularization, target-lesion revascularization) and safety (death, myocardial infarction, stent thrombosis) outcomes were evaluated and trial-level data pooled by both mixed-treatment comparison and direct comparison analyses. From 76 randomized clinical trials with 117 762 patient-years of follow-up, compared with BMS, each DES reduced long-term target-vessel revascularization (39%-61%), but the magnitude varied by DES type (EES∼SES∼ZES-R>PES∼ZES>BMS)), with a >42% probability that EES had the lowest target-vessel revascularization rate. There was no increase in the risk of any long-term safety outcomes, including stent thrombosis, with any DES (versus BMS). In addition, there was reduction in myocardial infarction (all DES except PES versus BMS) and stent thrombosis (with EES versus BMS: Rate ratio, 0.51; 95% credibility interval, 0.35-0.73). The safest DES appeared to be EES (>86% probability), with reduction in myocardial infarction and stent thrombosis compared with BMS. Short-term outcomes were similar to long-term outcomes, with SES, ZES-R, and everolimus-eluting stent being the most efficacious and EES being the safest stent. Conclusions--DES are highly efficacious at reducing the risk of target-vessel revascularization without an increase in any safety outcomes, including stent thrombosis. However, among the DES types, there were considerable differences, such that EES, SES, and ZES-R were the most efficacious and EES was the safest stent. [ABSTRACT FROM AUTHOR]