Polymer-based Drug-eluting Stents Research Articles

A Snapshot on Clinical Trials on Zotarolimus DES: A Repurposing Drug against Myocardial Infarction

AbstractMyocardial infarction is the permanent death (necrosis) of heart muscle caused by a lack of oxygen for an extended period of time (ischemia). Since the very first percutaneous transluminal coronary angioplasty was done 40 years ago, the science of interventional cardiology has advanced dramatically. The above progression began with a balloon catheter attached to a fixed wire, advancing to bare-metal stents, first-generation drug-eluting stents (DES), second- and third-generation biodegradable polymer-based DES. Ultimately, bioabsorbable stents are still in development. Zotarolimus is a new pharmacologic therapy with a similar reprint address; for example, the antirestenosis agent sirolimus has recently been investigated as part of a stent platform combined with a biomimetic phosphorylcholine and BioLINX polymer for its biological activity, as well as its usefulness as an antiproliferative agent. Several clinical trials have been conducted to assess the safety and efficacy of the zotarolimus drug-eluting stent (Z-DES). Medtronic Medical Devices, a global leader in medical technology (United States), and Abbot Global Health Care and Research began clinical trials on the Z-DES in 2002 and will continue through 2021 (INDIA). Endeavor (E-Zes), Resolute (R-Zes), Resolute Integrity (I-Zes), and Resolute Onyx are the different forms of Z-DES that Medtronic has tested in clinical trials. In comparison to other DES, Z-DES was found to be safe in these clinical trials done across multiple nations and in a diverse demographic. This review helps understand the overall clinical trial of Z-DES.

High-Dose Drug-Coated Balloon Versus Polymer-Based Drug-Eluting Stent for Femoropopliteal Artery Disease Treatment.

Clinical trials have demonstrated that high-dose drug-coated balloon (HD-DCB) and polymer-based drug-eluting stent (PB-DES) treatments for femoropopliteal (FP) artery disease have favorable outcomes. However, which one would be better remained unrevealed. This study used the databases of 2 large-scale multicenter prospective drug-coated balloon (DCB) and drug-eluting stent (DES) registries. The study included 2470 patients with symptomatic FP lesion treated with IN.PACT Admiral DCB or Eluvia DES at 69 centers. A propensity-score-based paired analysis was conducted. Primary endpoint was 1-year restenosis rate. Secondary endpoints were 1-year reocclusion rate, target lesion revascularization (TLR), acute thrombosis, bypass conversion, major amputation, major adverse limb event (MALE), and all-cause death. A total of 1535 patients were treated with HD-DCB, and 935 patients were treated with PB-DES. The propensity-score matching extracted 678 pairs, with no remarkable intergroup difference in baseline characteristics. The 1-year restenosis rate was significantly lower in the PB-DES group than in the HD-DCB group (16.0% vs 22.0%, p=0.016). The other endpoints (reocclusion rate, TLR, acute thrombosis, bypass conversion, major amputation, MALE, and all-cause death) did not differ between the groups. No baseline characteristics had any significant interaction effect on the association of HD-DCB vs PB-DES with restenosis risk (all p>0.05). This study demonstrated that the 1-year TLR, reocclusion rate, and other endpoints did not differ between the PB-DES group and the HD-DCB group despite the lower restenosis in the PB-DES group. One-year restenosis rate was significantly lower in the polymer-based DES group than in the high-dose DCB group for foemoropopliteal disease. However, there is no difference in the other endpoints between two groups.

Polymer-based drug-eluting stent treatment extends the time to reintervention for patients with symptomatic femoropopliteal artery disease: clinical evidence and potential economic value.

Aim: Use long-term follow-up data from the IMPERIAL study to determine whether drug-eluting polymer-based nitinol stent treatment can delay the time to repeat intervention for femoropopliteal artery disease and how such a delay may result in cost savings in a value-based episode of care. Patients & methods: The IMPERIAL randomized controlled trial was an international study of a paclitaxel-eluting polymer-coated stent (Eluvia, Boston Scientific, MA, USA) versus a polymer-free paclitaxel-coated stent (Zilver PTX, Cook Corporation, IN, USA) for treating lesions of the femoropopliteal arterial segment. Study patients (n=465) had symptomatic lower limb ischemia. Safety and efficacy assessments were performed through 5years. Mean time to first reintervention was calculated in post-hoc analysis for patients who underwent a clinically driven target lesion revascularization (CD-TLR) through 3 or 5years following the index procedure. To simulate potential cost savings associated with differential CD-TLR burden over time, a cost-avoidance analysis using input parameters from IMPERIAL and US 100% Medicare standard analytical files was developed. Results: Among patients with a first CD-TLR through 3years of follow-up, mean time to reintervention was 5.5months longer (difference 166days, 95% CI: 51, 282days; p=0.0058) for patients treated with Eluvia (n=56) than for those treated with Zilver PTX (n=30). Through the 5-year study follow-up period, CD-TLR rates were 29.3% (68/232) for Eluvia and 34.2% (39/114) for Zilver PTX (p=0.3540) and mean time to first reintervention exceeded 2years for patients treated with Eluvia at 737days versus 645days for the Zilver PTX group (difference 92days, 95% CI: -85, 269days; p=0.3099). Simulated savings considering reinterventions occurring over 1 and 5years following initial use of Eluvia over Zilver PTX were US $1,395,635 and US $1,531,795, respectively, when IMPERIAL CD-TLR rates were extrapolated to 1000 patients. Conclusion: IMPERIAL data suggest initial treatment with Eluvia extends the time patients spend without undergoing reintervention. This extension may be associated with cost savings in relevant time frames.

Preliminary Investigation on Efficacy and Safety of Substance P-Coated Stent for Promoting Re-Endothelialization: A Porcine Coronary Artery Restenosis Model.

Current polymer-based drug-eluting stents (DESs) have fundamental issues about inflammation and delayed re-endothelializaton of the vessel wall. Substance-P (SP), which plays an important role in inflammation and endothelial cells, has not yet been applied to coronary stents. Therefore, this study compares poly lactic-co-glycolic acid (PLGA)-based everolimus-eluting stents (PLGA-EESs) versus 2-methacryloyloxyethyl phosphorylcholine (MPC)-based SP-eluting stents (MPC-SPs) in in-vitro and in-vivo models. The morphology of the stent surface and peptide/drug release kinetics from stents were evaluated. The in-vitro proliferative effect of SP released from MPC-SP is evaluated using human umbilical vein endothelial cell. Finally, the safety and efficacy of the stent are evaluated after inserting it into a pig's coronary artery. Similar to PLGA-EES, MPC-SP had a uniform surface morphology with very thin coating layer thickness (2.074μm). MPC-SP showed sustained drug release of SP for over 2weeks. Endothelial cell proliferation was significantly increased in groups treated with SP (n = 3) compared with the control (n = 3) and those with everolimus (n = 3) (SP: 118.9 ± 7.61% vs. everolimus: 64.3 ± 12.37% vs. the control: 100 ± 6.64%, p < 0.05). In the animal study, the percent stenosis was higher in MPC-SP group (n = 7) compared to PLGA-EES group (n = 7) (MPC-SP: 28.6 ± 10.7% vs. PLGA-EES: 16.7 ± 6.3%, p < 0.05). MPC-SP group showed, however, lower inflammation (MPC-SP: 0.3 ± 0.26 vs. PLGA-EES: 1.2 ± 0.48, p < 0.05) and fibrin deposition (MPC-SP: 1.0 ± 0.73 vs. PLGA-EES: 1.5 ± 0.59, p < 0.05) around the stent strut. MPC-SP showed more increased expression of cluster of differentiation 31, suggesting enhanced re-endothelialization. Compared to PLGA-EES, MPC-SP demonstrated more decreased inflammation of the vascular wall and enhanced re-endothelialization and stent coverage. Hence, MPC-SP has the potential therapeutic benefits for the treatment of coronary artery disease by solving limitations of currently available DESs.

Hypoechoic Halo Imaging Findings Following Femoropopliteal Artery Stent Implantation: Risk Factors and Clinical Outcomes

BackgroundHypoechoic peri-stent areas in duplex ultrasonography (DUS) (ie, “halo”) have been noted following femoropopliteal artery stenting. ObjectivesThis study sought to investigate the prevalence, risk factors, and potential safety implications of hypoechoic halos identified with DUS following stent implantation in the IMPERIAL (ELUVIA Drug-Eluting Stent Versus Zilver PTX Stent) and EMINENT (Trial Comparing ELUVIA Versus Bare Metal Stent in Treatment of Superficial Femoral and/or Proximal Popliteal Artery) trials. MethodsThe IMPERIAL and EMINENT studies of femoropopliteal artery stenting included polymer-based drug-eluting stent, nonpolymer drug-coated stent, and bare metal stent treatment arms. A dedicated DUS protocol was implemented for core laboratory assessment of halo presence at study follow-up visits. Logistic regressions were used to investigate risk factors for a halo sign and its impact on clinically driven target lesion revascularization and primary patency. ResultsDiagnostic DUS imaging from 659 patients was obtained at time points ranging from 6 months to 5 years post–stent implantation. Halo prevalence ranged from 20% to 35% of patients with diagnostic DUS and was present at all time intervals. Halos were identified surrounding all stent types. In analyses of patients with diagnostic imaging from at least 2 visits, halo presence typically persisted, with occasional cases of regression and development at later times. No statistically significant association was found for halo status (ie, halo vs no halo) on 1-year clinically driven target lesion revascularization (OR: 1.27; 95% CI: 0.70-2.30; P = 0.4240) or primary patency (OR: 0.68; 95% CI: 0.43-1.07; P = 0.0927). ConclusionsA hypoechoic halo following a femoropopliteal stent procedure is a common occurrence associated with all studied stent types. The presence of a halo appears to be benign with no associated clinical sequelae or effect on target vessel revascularization rates within 1 year of stent implantation.

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

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

Late neointimal volume reduction is observed following biodegradable polymer-based drug eluting stent in porcine model.

BackgroundThe BP-SES has an abluminally applied biodegradable polymer that is fully resorbed after 3–4 months but may have longer-lasting effects. The aim of this study was to determine the long-term vascular response to the novel Ultimaster™ sirolimus-eluting stent (BP-SES).MethodsBP-SESs, everolimus-eluting stents (DP-EESs), and bare metal stents were implanted in 22 coronary arteries of 15 mini-swine. All animals underwent optical frequent domain imaging (OFDI) to assess neointimal volume and quality at either 1 (n = 7) or 3 (n = 8) months and at 9 (n = 15) months and were euthanized at 9 months. Stents were subsequently histologically investigated to analyze the vascular response and maturity of neointimal tissue according to cell density.ResultsOFDI revealed greater regression in neointimal volume from 3 to 9 months with BP-SESs than with DP-EESs (−0.6 ± 0.5 mm2 vs. 0.00 ± 0.4 mm2, p = 0.07). Although there was no significant difference between BP-SESs and DP-EESs in the inflammation score (BMS, BP-SES, and DP-EES: 0.1 ± 0.1, 0.3 ± 0.4, and 0.4 ± 0.4, respectively; p < 0.0001) in histological analysis, BP-SESs showed slightly greater maturity than DP-EESs (1.8 ± 0.3, 1.7 ± 0.3, and 1.6 ± 0.3, p = 0.09).ConclusionsWhile both BP-SESs and DP-EESs showed minimal inflammatory responses at 9 months, BP-SESs showed a trend for greater neointimal maturity and regression, which may be related to earlier completion of the vascular response.

2-Year Outcomes of the Eluvia Drug-Eluting Stent for the Treatment of Complex Femoropopliteal Lesions.

The aim of this study was to evaluate the 2-year performance of a polymer-based drug-eluting stent (DES) for the treatment of complex femoropopliteal lesions. Despite the promising early outcomes of the Eluvia DES, the long-term safety and efficacy of the device in a real-world scenario remain unclear. Between March 2016 and December 2018, 130 patients (137 lesions) with symptomatic femoropopliteal disease were included in this study. The primary outcome measure of this analysis was primary patency. Secondary patency, freedom from target lesion revascularization, freedom from surgical conversion, and overall mortality and morbidity were additionally analyzed. The majority of patients presented with lifestyle-limiting claudication (n=90 [69%]). The mean lesion length was 194 ± 108mm, 74% of the lesions (n=101) were chronic total occlusions, and 72% (n=99) were calcified. Moderate to severe calcification (Peripheral Arterial Calcium Scoring Scale score 3 or 4) was observed in 48% of the treated vessels (n=67). At 24months, the Kaplan-Meier estimate of primary patency was 71%, whereas both the secondary patency rate and freedom from target lesion revascularization were 80%. Overall survival amounted to 85%. Freedom from major amputation was 98%, while freedom from surgical conversion was 89%. Degeneration of the vessel wall was observed in 27 lesions (20%). In this study, use of the Eluvia polymer-based DES for the treatment of complex femoropopliteal disease showed promising 2-year results. Nonetheless, a relatively high rate of vessel wall degeneration was observed after DES deployment.

Polymer-based or Polymer-free Stents in Patients at High Bleeding Risk

BackgroundPolymer-free drug-coated stents provide superior clinical outcomes to bare-metal stents in patients at high bleeding risk who undergo percutaneous coronary intervention (PCI) and are treated with 1 month of dual antiplatelet therapy. Data on the use of polymer-based drug-eluting stents, as compared with polymer-free drug-coated stents, in such patients are limited.MethodsIn an international, randomized, single-blind trial, we compared polymer-based zotarolimus-eluting stents with polymer-free umirolimus–coated stents in patients at high bleeding risk. After PCI, patients were treated with 1 month of dual antiplatelet therapy, followed by single antiplatelet therapy. The primary outcome was a safety composite of death from cardiac causes, myocardial infarction, or stent thrombosis at 1 year. The principal secondary outcome was target-lesion failure, an effectiveness composite of death from cardiac causes, target-vessel myocardial infarction, or clinically indicated target-lesion revascularization. Both outcomes were powered for noninferiority.ResultsA total of 1996 patients at high bleeding risk were randomly assigned in a 1:1 ratio to receive zotarolimus-eluting stents (1003 patients) or polymer-free drug-coated stents (993 patients). At 1 year, the primary outcome was observed in 169 of 988 patients (17.1%) in the zotarolimus-eluting stent group and in 164 of 969 (16.9%) in the polymer-free drug-coated stent group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% confidence interval [CI], 3.5; noninferiority margin, 4.1; P=0.01 for noninferiority). The principal secondary outcome was observed in 174 patients (17.6%) in the zotarolimus-eluting stent group and in 169 (17.4%) in the polymer-free drug-coated stent group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% CI, 3.5; noninferiority margin, 4.4; P=0.007 for noninferiority).ConclusionsAmong patients at high bleeding risk who received 1 month of dual antiplatelet therapy after PCI, use of polymer-based zotarolimus-eluting stents was noninferior to use of polymer-free drug-coated stents with regard to safety and effectiveness composite outcomes. (Funded by Medtronic; ONYX ONE ClinicalTrials.gov number, NCT03344653.)

Validation of the long-term prognostic capability of the SYNTAX score II in patients undergoing biodegradable polymer-based Sirolimus-eluting stents: 2-year outcomes from the PANDA III trial

BackgroundThis study aimed to assess the prognostic ability of SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) Score II (SS-II) in LM and/or TVD patients undergoing biodegradable polymer-based drug-eluting stents (BP-DES) in the multi-central randomized PANDA III trial. MethodsA total of 723 patients in PANDA III population were enrolled in this study. According to SS-II tertiles, patients were stratified as follow: SS-II ≤ 23 (n = 224), 23 < SS II ≤ 31 (n = 255), SS II > 31 (n = 244). The predictive abilities for 2-year cardiac death were compared between angiographic scores and scores combining both angiographic and clinical variables. ResultsMean anatomic SS was 20.6 ± 9.4, SS-II for PCI was 28.7 ± 8.6. During 2-year follow up, cardiac death (0.00% vs. 1.7% vs. 4.3%, p = 0.003) and target lesion failure (5.9% vs. 9.1% vs. 13.6%, p = 0.020) was significantly higher in the upper tertile group than in intermedian and low tertile. At multivariate analysis, SS-II for PCI was an independent risk factor of cardiac death (Hazard ratio: 2.41, 95%CI: 1.47–3.97, p < 0.005) and TLF (Hazard ratio: 1.29, 95%CI: 1.01–1.65, p = 0.040). The ROC curve analysis showed that SS-II for PCI had better ability than other SYNTAX scoring systems to predict cardiac death (AUC: 0.746, 95%CI:0.63–0.87, p = 0.010). ConclusionsThe SS-II had superiority than other SYNTAX scoring systems in predicting 2-year cardiac death in LM and/or TVD patients undergoing PCI with biodegradable polymer drug-eluting stents.

P3393Comparison of intermediate-term vascular response to new-generation biodegradable polymer and durable polymer-based drug-eluting stents: optical coherence tomographic study

Abstract Background Over the last decade, drug-eluting stents (DES) have undergone substantial modifications with thinner struts and more biocompatible durable polymer (DP) or biodegradable polymer (BP). In DP-based DES, after drug elusion has been completed, DP remnants may trigger of local inflammatory vascular reactions and promote delayed healing, leading to accelerated neoatherosclerosis (NA). Thus, BPs have been developed to reduce the above-mentioned risks. Recently, poor strut coverage and in-stent NA are increasingly recognized the cause of late stent failure, but it is unclear whether BPs can reduce the incidence of NA and the poor stent coverage as compared to DPs. Objectives The purpose of this study was to compare the incidence of NA and the stent coverage using optical coherence tomography (OCT) between the DPs and the BPs. Methods Between July 2016 and April 2018, 127 consecutive patients with new-generation DES who underwent 8-month follow up OCT imaging were enrolled. Patients were divided into the two groups: DP group who had the new-generation durable polymer everolimus-eluting and zotarolimus-eluting stents and BP group who had the new-generation biodegradable polymer sirolimus-eluting and everolimus-eluting stents. We compared patient characteristics including hypertension, dyslipidemia and diabetes mellitus and 8-month follow up OCT findings including NA, uncovered struts and malapposed struts between the two groups. Results The DP group comprised 64 patients (50.4%. The incidence of NA, uncovered struts and malapposed struts were similar between the two groups (DPs vs BPs, 1.56% vs 7.94%, P=0.11; 7.80% vs 5.88%, P=0.16 and 2.76% vs 2.01%, P=0.43, respectively) (table). The other parameters were also similar between the two groups. Table 1 DP group (n=64) BP group (n=63) P value Hypertension 44 (68.8%) 50 (79.4%) 0.2251 Dyslipidemia 39 (60.9%) 37 (58.7%) 0.8573 Diabetes mellitus 25 (39.1%) 30 (47.6%) 0.3731 8 month OCT follow up findings Neoatherosclerosis 1 (1.6%) 5 (7.9%) 0.1147 Uncovered struts 7.8% (2.8–20.4) 5.9% (0.7–16.7) 0.1616 Malapposed struts 0.2% (0–2.8) 0% (0–2.8) 0.4392 Conclusions The new-generation DP based-DES may have similar effects on vascular response compared to the new-generation BP-based DES during 8-month follow-up period.

Comparisons of early vascular reactions in biodegradable and durable polymer-based drug-eluting stents in the porcine coronary artery

Current drug-eluting stents have abluminal polymer coating; however, thrombus formation in these compared with that in uniformly coated stents remains controversial. We evaluated thrombus formation and early endothelialization after using abluminal biodegradable polymer-coated sirolimus- (BP-SES), and everolimus-eluting stents (BP-EES) versus a durable polymer-coated everolimus-eluting stent (DP-EES) in an in vivo setting. BP-SES, BP-EES, and DP-EES (n = 6 each) were implanted in coronary arteries of 12 mini-pigs that were then sacrificed after 7 and 10 days. Stents were stained with hematoxylin and eosin, and a combined Verhoeff and Masson trichrome stain. Areas of fibrin deposition were digitally detected and measured with off-line morphometric software. Stents were investigated for re-endothelialization by transmission electron microscopy. At 7 days, histological analysis revealed the lowest area of fibrin deposition in BP-SES (BP-SES vs. BP-EES vs. DP-EES; 0.10 ± 0.06 mm2 vs. 0.15 ± 0.07 mm2 vs. 0.19 ± 0.06 mm2, p = 0.0004). At 10 days, the area of fibrin deposition was significantly greater in DP-EES (0.13 ± 0.04 mm2 vs. 0.14 ± 0.05 mm2 vs. 0.19 ± 0.08 mm2, p = 0.007). Endothelial cells in BP-SES demonstrated a significantly greater number of tight junctions than those in DP-EES according to by transmission electron microscopy for both days (p<0.05). Various parameters, including an inflammatory reaction and neointimal formation, were comparable among the groups at 7 and 10 days. An abluminal biodegradable polymer-coated SES showed the least fibrin deposition and greatest endothelial cell recovery at an early stage following implantation in the coronary arteries of mini-pigs.

40 Years of Percutaneous Coronary Intervention: History and Future Directions

The field of interventional cardiology has evolved significantly since the first percutaneous transluminal coronary angioplasty was performed 40 years ago. This evolution began with a balloon catheter mounted on a fixed wire and has progressed into bare-metal stents (BMS), first-generation drug-eluting stents (DES), second- and third-generation biodegradable polymer-based DES, and culminates with the advent of bioabsorbable stents, which are currently under development. Each step in technological advancement has improved outcomes, while new persisting challenges arise, caused by the stent scaffolds, the polymers employed, and the non-selective cytostatic and cytotoxic drugs eluted from the stents. Despite the promising technological advances made in stent technology, managing the balance between reductions in target lesion revascularization, stent thrombosis, and bleeding remain highly complex issues. This review summarizes the evolution of percutaneous coronary intervention with a focus on vascular dysfunction triggered by the non-selective drugs eluted from various stents. It also provides an overview of the mechanism of action of the drugs currently used in DES. We also discuss the efforts made in developing novel cell-selective drugs capable of inhibiting vascular smooth muscle cell (VSMC) proliferation, migration, and infiltration of inflammatory cells while allowing for complete reendothelialization. Lastly, in the era of precision medicine, considerations of patients’ genetic variance associated with myocardial infarction and in-stent restenosis are discussed. The combination of personalized medicine and improved stent platform with cell-selective drugs has the potential to solve the remaining challenges and improve the care of coronary artery disease patients.

Sustained drug release using cobalt oxide nanowires for the preparation of polymer-free drug-eluting stents.

Polymer-based drug-eluting stents (DESs) represented attractive application for the treatment of cardiovascular diseases; however, polymer coating has caused serious adverse responses to tissues such as chronic inflammation due to acidic by-products. Therefore, polymer-free DESs have recently emerged as promising candidates for the treatment; however, burst release of drug(s) from the surface limited its applications. In this study, we focused on delivery of therapeutic drug from polymer-free (or -less) DESs through surface modification using cobalt oxide nanowires (Co3O4 NWs) to improve and control the drug release. The results demonstrated that Co3O4 NWs could be simply fabricated on cobalt-chromium substrate by ammonia-evaporation-induced method. The Co3O4 NWs were uniformly arrayed with diameters of 50-100 nm and lengths of 10 µm. It was found that Co3O4 NWs were comparatively stable without any delamination or change of the morphology under in vitro long-term stability using circulating system. Sirolimus was used as a model drug for studying in vitro release behavior under physiological conditions. The sirolimus release behavior from flat cobalt-chromium showed an initial burst (over 90%) after one day. On the other hand, Co3O4 NWs presented a sustained sirolimus release rate for up to seven days. Similarly, the polymer-less specimens on Co3O4 NWs substrates sustained sirolimus release for a longer-period of time when compared to flat Co-Cr substrates. In summary, the current approach of using Co3O4 NWs-based substrates might have a great potential to sustain drug release for drug-eluting implants and medical devices including stents.

In vitro and in vivo evaluation of a novel polymer-free everolimus-eluting stent by nitrogen-doped titanium dioxide film deposition

Inflammation and thrombosis are linked to the use of polymer-based drug-eluting stents (DES). The aim of this study was to develop a polymer-free everolimus (EVL)-eluting stent using nitrogen-doped titanium dioxide (N-TiO2) and verify its efficacy by in vitro and in vivo assessment in a porcine coronary model. Various analytical approaches such as scanning electron microscopy and atomic force microscopy, electron spectroscopy, Fourier transform infrared spectrometry and contact angle measurement were employed for the characterization. As a part of biocompatibility assessment, platelet adhesion and smooth muscle cell (SMC) proliferation were examined. Bare metal stent (BMS), N-TiO2 stent, everolimus-eluting N-TiO2 (N-TiO2-EVL) stent, and commercialized EVL-eluting stent (EES) were randomly placed in forty coronary arteries in twenty pigs. After four weeks of implantation, the stents were subjected to histological and quantitative analysis. The N-TiO2 film used in this study was well coated without any cracks or peeling. Surface hydrophilicity (88.8% of angle decrement) could be associated with the decrease in surface roughness post N-TiO2 deposition (37.0%). The platelet adhesion on the N-TiO2 surfaces was less than that on the BMS surface. The proliferation of SMC was suppressed in the N-TiO2-EVL group (30.2%) but not in the BMS group. In the animal study, the percent area restenosis was significantly decreased in the N-TiO2-EVL group compared to that in the BMS group. The results (BMS; 47.0 ± 11.00%, N-TiO2-EVL; 31.7 ± 10.50%, and EES; 29.1 ± 11.21%, n = 10, p < 0.05) were almost at par with those of the commercialized EVL-eluting stent. The introduction of N-TiO2 deposition during fabrication of polymer-free DES may be an efficient accessorial process for preventing in-stent restenosis and thrombosis.

2925Four-year clinical outcome following randomised use of zotarolimus-eluting stents versus everolimus-eluting stents in all-comers: insights from the DUTCH PEERS trial

Background: The DUTCH PEERS (TWENTE II) trial (clinicaltrials.gov NCT01331707) is a randomised, multicenter, single-blinded, investigator initiated all-comers trial. All coronary syndromes were permitted with no limit for lesion length, reference size, or number of lesions or diseased vessels to be treated. In total, 1811 patients were 1:1 randomised to cobalt chromium-based zotarolimuseluting stents (ZES) versus platinum chromium-based everolimus-eluting stents (EES). These durable polymer-based drug-eluting stents (DES) were developed to facilitate device deliverability and to improve stent apposition to the vessel wall. Purpose: We assessed the 4-year clinical outcome of the DUTCH PEERS trial in terms of safety and efficacy. Methods: Clinical outcome was assessed by means of follow-up data of the trial participants. The primary endpoint target vessel failure (TVF) is a composite of cardiac death, target vessel-related myocardial infarction (MI) or target vessel revascularization. Secondary endpoints included the individual components of the TVF and the incidence of definite-or-probable stent thrombosis. Endpoints were analyzed by the logrank test by comparing the time to the endpoint, using the Kaplan-Meier method. Independent contract research organizations performed the study monitoring and clinical event adjudication. Results: The 4-year clinical follow-up data were available in 1802 patients (99.5%; 4 patients were lost to follow-up and 5 withdrew consent). The ZES and EES groups showed favourable outcomes with a similar incidence of TVF (12.1% vs. 12.1%; Logrank p=0.95). The rates of the individual components of TVF were also similar for both stent arms: cardiac death (3.9% vs. 3.7%; Logrank p=0.78); target vessel-related MI (3.2% vs. 2.5%; Logrank p=0.38); and target vessel revascularization (6.8% vs. 7.5%; Logrank p=0.55), respectively. In addition, the incidence of definite-or-probable stent thrombosis was similar for patients treated with ZES versus EES (1.5% vs. 1.2%; Logrank p=0.67). Conclusion: At 4-year follow-up, ZES and EES showed similar and sustained results in terms of safety and efficacy for treating all-comer patients.

Safety and Efficacy of New Biodegradable Polymer-based Sirolimus-Eluting Stents in a Preclinical Model

Introduction and objectivesNew drug-eluting stents (DES) designed to overcome the limitations of existing devices should initially be tested in preclinical studies. Our objective was to analyze the safety and efficacy of new biodegradable polymer-based DES compared with bare-metal stents (BMS) and commercially available DES in a model of normal porcine coronary arteries. MethodsWe randomly implanted 101 stents (BMS and biodegradable polymer-based sirolimus-eluting stents: 3 test stent iterations [BD1, BD2, and BD3], Orsiro, Biomime and Biomatrix) in the coronary arteries of 34 domestic pigs. Angiographic and histomorphometric studies were conducted 1 month (n = 83) and 3 months (n = 18) later. ResultsThe stents were implanted at a stent/artery ratio of 1.31 ± 0.21, with no significant differences between groups. At 1 month, the new test stents (BD1, BD2 and BD3) showed less late loss and angiographic restenosis, as well as lower histologic restenosis and neointimal area (P < .0005), than the BMS. There were no differences in endothelialization, vascular injury, or inflammation between the new test stents and BMS, although the new stents showed higher fibrin deposition (P = .0006). At 3 months, all these differences disappeared, except for a lower neointimal area with the new BD1 stent (P = .027). No differences at any time point were observed between the new test stents and commercially available controls. ConclusionsIn this preclinical model, the new biodegradable polymer-based DES studied showed less restenosis than BMS and no significant differences in safety or efficacy vs commercially available DES.

Long-term preclinical evaluation of bioabsorbable polymer-coated drug-eluting stent in a porcine model

Bioabsorbable polymer-based drug-eluting stents have been shown to be effective and safe in the actual practice. The objective of the present study was to evaluate a biodegradable poly-L-lactic acid (PLLA)-based sirolimus-coated stent in comparison with a commercial everolimus-eluting stent with a permanent polymer in a porcine coronary restenosis model on a short-, mid-, and long-term basis. Pigs were randomized into eight groups in which the coronary arteries (36 pigs with 72 coronary arteries) had either a sirolimus-eluting stent with PLLA (SES, n=24, follow-up after 4, 12, and 24 weeks), bare metal stent (BMS, n=12, follow-up after 4 weeks), PLLA-coated stent without a drug (PCS, n=12, follow-up after 4 weeks), or commercial everolimus-eluting stent with a permanent polymer (EES, Promus PREMIER®, n=24, follow-up after 4, 12, and 24 weeks). Histopathological analysis was performed at 4, 12, or 24 weeks after stenting. The surface morphology of the SES, visualized using an optical microscope and a scanning electron microscope, was smooth and uniform with virtually no defects. Sirolimus was released slowly over 60 days. There was no significant difference in the percent area stenosis between the SES and EES at any of the follow-up time points (13.0±8.10% in SES vs. 14.1±9.12% in EES at 4 weeks, 23.1±8.63% in SES vs. 21.3±7.92% in EES at 12 weeks, 28.2±8.20% in SES vs. 25.1±8.51% in EES at 24 weeks, each p=NS). The percent area stenosis using micro-computed tomography and intravenous ultrasound demonstrated similar restenosis rates with histopathological stenosis between the SES and EES. The SES with a biodegradable polymer was as effective as the commercial EES with a permanent polymer in inhibiting neointima proliferation at 4, 12, and 24 weeks in a porcine coronary restenosis model.

Seguridad y eficacia de nuevos modelos de stents liberadores de sirolimus con polímero biodegradable en el modelo preclínico

Introduction and objectivesNew drug-eluting stents (DES) designed to overcome the limitations of existing devices should initially be tested in preclinical studies. Our objective was to analyze the safety and efficacy of new biodegradable polymer-based DES compared with bare-metal stents (BMS) and commercially available DES in a model of normal porcine coronary arteries. MethodsWe randomly implanted 101 stents (BMS and biodegradable polymer-based sirolimus-eluting stents: 3 test stent iterations [BD1, BD2, and BD3], Orsiro, Biomime and Biomatrix) in the coronary arteries of 34 domestic pigs. Angiographic and histomorphometric studies were conducted 1 month (n = 83) and 3 months (n = 18) later. ResultsThe stents were implanted at a stent/artery ratio of 1.31 ± 0.21, with no significant differences between groups. At 1 month, the new test stents (BD1, BD2 and BD3) showed less late loss and angiographic restenosis, as well as lower histologic restenosis and neointimal area (P < .0005), than the BMS. There were no differences in endothelialization, vascular injury, or inflammation between the new test stents and BMS, although the new stents showed higher fibrin deposition (P = .0006). At 3 months, all these differences disappeared, except for a lower neointimal area with the new BD1 stent (P = .027). No differences at any time point were observed between the new test stents and commercially available controls. ConclusionsIn this preclinical model, the new biodegradable polymer-based DES studied showed less restenosis than BMS and no significant differences in safety or efficacy vs commercially available DES.Full English text available from:www.revespcardiol.org/en

Polymer-Free Drug-Coated Coronary Stents in Patients with Stable Coronary Artery Disease at High Bleeding Risk.

Patients with stable coronary artery disease (CAD) and a high risk of bleeding are not ideal candidates for a polymer-based drug-eluting stent (DES) because it requires 6-12months of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI). The purpose of this review is to assess the angiographic and clinical outcomes of polymer-free drug-coated stents (PF-DCS) in stable CAD patients with a high bleeding risk. Several randomized controlled trials (RCTs) have compared angiographic and clinical outcomes of PF-DCS with bare-metal stents (BMS), permanent polymer (PP)-DES, or biodegradable polymer (BP)-DES. However, none of these studies particularly recruited patients with stable CAD and a high risk of bleeding. Furthermore, there are limited data available on duration of DAPT following PF-DCS placement. PF-DCS has a better efficacy and similar safety as compared with BMS. PF-DCS with dual drug is noninferior to currently available PP-DES. Further RCTs are needed to assess the safety and efficacy of PF-DCS to BP-DES and PP-DES comparing shorter to standard durations of DAPT.