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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.

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: 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.

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.

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

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 Background We evaluated the effectiveness and safety of a zotarolimus-eluting (ZES) versus a sirolimus-eluting (SES) coronary stent in a large cohort of patients treated with one of these stents in Western Denmark. Methods A total of 6,122 patients treated with ZES (n=2,282) or SES (n=3,840) were followed for up to 27 months. We ascertained clinical outcomes based on national medical databases. Results Incidence of target lesion revascularization (no. per 100 person-years) was 5.3 in the ZES group compared to 1.9 in the SES group (adjusted hazard ratio (HR)=2.19, 95% confidence intervals (CI): 1.39-3.47; p=0.001). All-cause mortality was also higher in the ZES group (ZES: 6.3; SES: 3.3; adjusted HR=1.34, 95% CI: 1.05-1.72; p=0.02), while stent thrombosis (ZES: 1.2; SES: 0.5; adjusted HR=1.98, 95% CI: 0.75-5.23; p=0.14) did not differ significantly. Conclusions In agreement with previously published randomised data, this observational study indicated that the ZES was associated with an increased risk of death and TLR in a large cohort of consecutive patients.