Paclitexel versus sirolimus-coated balloon in the treatment of coronary instent restenosis.

BACKGROUND: Few studies compared paclitaxel-coated balloon (PCB) versus sirolimus-coated balloon (SCB) in the treatment of drug-eluting stent (DES) instent restenosis (ISR). METHODS: Between November 5, 2009, and October 14, 2020, in our center 212 patients with first DES-ISR were treated with PCB (Restore®; Cardionovum GmbH, Bonn, Germany), whereas 230 patients were treated with SCB (Devoir®; MINVASYS SAS, Gennevilliers, France). Following a propensity matching, 186 patients were included into PCB group (PCB group), and in the SCB group (SCB group). The primary purpose of the study was the 1-year target lesion failure (TLF) rate, including cardiac death, target vessel-related myocardial infarction, and repeated target lesion or target vessel revascularization. RESULTS: Procedural success occurred in all cases. Fully optimal predilation (that is, balloon-to-stent ratio >0.91, time of DCB inflation >60 sec, and residual percent diameter stenosis after lesion preparation <20%) was observed more often in the SCB group (126 [68%] patients versus 106 [57%] patients; P=0.042). One-year TLF occurred in 29 (15.5%) patients in the SCB group and in 32 (17%) patients in the PCB group (OR=1.12 [0.65-1.95]; P=0.78). By logistic Cox regression analysis fully optimal predilation (OR=0.06; 95% CI: 0.01-0.21; P<0.001) but not DCB type (OR=0.74; 95% CI: 0.41-1.31; P=0.29) was independent predictor of 1-year TLF. CONCLUSIONS: The current study suggests that 1-year TLF is not statistically and clinically different in patients with DES ISR treated with a PCB and a SCB.

Rapamycin and Paclitaxel Affect Human Aortic Smooth Muscle Cells-Derived Foam Cells Viability and Proliferation.

INTRODUCTION: Drug-eluting stents (DES) coated with rapamycin or paclitaxel as antiproliferative substances significantly reduced the incidence of clinical restenosis and had fewer side effects after percutaneous coronary intervention. However, DES coated with rapamycin or paclitaxel still cause restenosis due to abnormal tissue growth which remained a therapeutic problem, particularly in certain subgroups, possibly due to drug concentrations. This study examined the impact of different concentrations of rapamycin and paclitaxel on cytokine, cell viability and proliferation in human aortic smooth muscle cells (HASMC)-derived foam cells. METHODS: The foam cell model was established in vitro by incubating HASMC with 20 µg/mL oxidized low-density lipoprotein (ox-LDL) for 48 hours. Subsequently, foam cells were treated with different concentrations (0.01 µg/mL, 0.1 µg/mL, 0.5 µg/mL, 1 µg/mL, 5 µg/mL and 10 µg/mL) of rapamycin or paclitaxel for 48 hours, to measure cytokine, cell viability and proliferation by ELISA and MTT, respectively. Finally, viability and proliferation were measured by MTT after the foam cells were treated with 1 µg/mL rapamycin or paclitaxel combined with cytokine antibody for 48 hours. RESULTS: After incubation of HASMC with ox-LDL, the ratios of cholesterol ester and total cholesterol increased significantly (55.29%) (P<0.01). Lipid staining with Oil Red O showed many lipid vacuoles and red dye particles in the cells. Meanwhile, cell viability and proliferation significantly increased compared with the control. This indicated that HASMC had been transformed into foam cells (P<0.01) while rapamycin or paclitaxel concentrations ≥0.1 µg/mL can significantly decrease the foam cell proliferation (P<0.05 or P<0.01), and 1 µg/mL of rapamycin or paclitaxel appeared the most effective concentration. As for cytokines, rapamycin or paclitaxel concentrations ≥1 ug/mL could significantly increase the level of inflammatory cytokines IL-6 (P<0.05 or P<0.01), which was enhanced with the increase of drug concentration. However, rapamycin or paclitaxel concentrations ≥1 µg/mL could significantly reduce the levels of anti-inflammatory cytokines IL-35 and transforming growth factor beta (TGF-ß) (P<0.05 or P<0.01), which decreased with the increase of drug concentration. In addition, rapamycin or paclitaxel combined with anti-IL-1ß, anti-IL-6, anti- TNF-α or anti-IL-35 had no significant effect on foam cell proliferation compared to the drug alone. However, rapamycin or paclitaxel combined with anti-IL-10 or anti-TGF-ß can significantly enhance foam cell proliferation (P<0.01). In addition, there was no difference in the effects of the same concentrations of rapamycin and paclitaxel on foam cells. CONCLUSION: Although rapamycin or paclitaxel can reduce foam cell proliferation, too high or too low concentrations could decrease effectiveness. In particular, a high dose can induce foam cells to increase inflammatory cytokines secretion, reduce anti-inflammatory cytokines secretion, and thus affect the inhibiting proliferation. For rapamycin- and paclitaxel-eluting stents, this conclusion may explain the clinical observation of in-stent restenosis after percutaneous coronary intervention. DES coated with an appropriate concentration of rapamycin or paclitaxel may, at least to some extent, contribute significantly to reducing incidence of late in-stent restenosis.

Association of Decreased Docosahexaenoic Acid Level After Statin Therapy and Low Eicosapentaenoic Acid Level with In-Stent Restenosis in Patients with Acute Coronary Syndrome.

AIM: It is speculated that statin therapy modulates the synthesis of polyunsaturated fatty acids (PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, the data available on the effects of statin therapy on the serum levels of PUFA and the subsequent impact on in-stent restenosis (ISR) in patients with acute coronary syndrome (ACS) are limited. METHODS: A total of 120 ACS patients who received emergent coronary stent implantation, follow-up coronary angiography to evaluate ISR, and new statin therapy were enrolled. We measured the serum levels of the PUFA and lipids at the onset of ACS and at the follow-up coronary angiography. RESULTS: The follow-up coronary angiography revealed 38 ISR cases. New statin therapy significantly reduced the serum levels of DHA and low-density lipoprotein cholesterol (LDL-C), while it did not affect EPA level. Single regression analysis revealed that a decreased serum level of LDL-C was associated with decreased DHA level. The multiple logistic regression analysis revealed that the decreased DHA level after statin therapy and low serum level of EPA on admission were determinants of prevalence of ISR. CONCLUSION: Statin therapy decreased the serum level of DHA with a parallel reduction in LDL-C level in patients with ACS. Decreased DHA level after statin therapy and low EPA level on admission are risk factors for ISR, indicating that in patients with ACS, decreased serum levels of DHA may be a residual target for the prevention of ISR.

Effects of ticagrelor on neointimal hyperplasia and endothelial function, compared with clopidogrel and prasugrel, in a porcine coronary stent restenosis model.

BACKGROUND: Several investigations have been conducted to evaluate the off-target effects of ticagrelor. The aim of the present study was to evaluate the off-target effects of ticagrelor such as neointimal formation and endothelial function after drug-eluting stent implantation in a porcine restenosis model. METHODS: A total of 30 pigs were randomly allocated based on the following P2Y12 inhibitor: (1) clopidogrel 300mg loading plus 75mg maintenance (n=10); (2) prasugrel 60mg loading plus 10mg maintenance (n=10); (3) ticagrelor 180mg loading plus 180mg maintenance (n=10). In each group, zotarolimus-eluting stents were implanted in the proximal portion of the left anterior descending artery and left circumflex artery. One month after stenting, the animals underwent follow-up angiography, endothelial function assessment, optical coherence tomography (OCT) and histopathological analysis. RESULTS: Regarding vasomotor responses to acetylcholine infusion, there were significant vasoconstrictions to maximal acetylcholine infusion in the clopidogrel and prasugrel group compared with those in the ticagrelor group. The mean neointimal area were significantly lower in the ticagrelor group (1.0±0.3 by OCT, 0.9±0.3 by histology), than in the clopidogrel (1.8±0.7, p=0.003, 1.6±0.8, p=0.030) and prasugrel (1.8±0.5, p=0.001, 1.5±0.5, p=0.019) groups. Percentages of moderate to dense peri-strut inflammatory cell infiltration were significantly lower in the ticagrelor group (9.0%) compared with the clopidogrel (17.3%, p<0.001) and prasugrel groups (15.7%, p=0.002). There were no significant differences in all findings between clopidogrel and prasugrel groups. CONCLUSIONS: Compared to clopidogrel and prasugrel, ticagrelor reduced neointimal formation, endothelial dysfunction, and peri-strut inflammation.

Cocaine-induced very late stent thrombosis.

Cocaine misuse is a known cause of acute coronary syndrome (ACS). Management of these patients has always been a challenge due to medication compliance and eventual risk of stent thrombosis. However, even cocaine misusers who are compliant with dual antiplatelet therapy have been reported to have stent thrombosis. All cases of cocaine-induced stent thrombosis reported in the literature have occurred within first year of stent placement (acute, subacute or late). We report a first case of very late stent thrombosis in a 54-year-old active cocaine misuser who presented with ST segment elevation myocardial infarction, which was successfully managed with percutaneous transluminal coronary angioplasty. A review of all the reported cases of cocaine-induced stent thrombosis is also discussed. Given the high mortality associated with stent thrombosis, treatment option for cocaine misusers presenting with ACS should be conservative when possible. If percutaneous coronary intervention is needed, bare metal stent should be preferred.

Secreted Matrix Metalloproteinase-9 of Proliferating Smooth Muscle Cells as a Trigger for Drug Release from Stent Surface Polymers in Coronary Arteries.

Cardiovascular diseases are the leading causes of death in industrialized countries. Atherosclerotic coronary arteries are commonly treated with percutaneous transluminal coronary intervention followed by stent deployment. This treatment has significantly improved the clinical outcome. However, triggered vascular smooth muscle cell (SMC) proliferation leads to in-stent restenosis in bare metal stents. In addition, stent thrombosis is a severe side effect of drug eluting stents due to inhibition of endothelialization. The aim of this study was to develop and test a stent surface polymer, where cytotoxic drugs are covalently conjugated to the surface and released by proteases selectively secreted by proliferating smooth muscle cells. Resting and proliferating human coronary artery smooth muscle cells (HCASMC) and endothelial cells (HCAEC) were screened to identify an enzyme exclusively released by proliferating HCASMC. Expression analyses and enzyme activity assays verified selective and exclusive activity of the matrix metalloproteinase-9 (MMP-9) in proliferating HCASMC. The principle of drug release exclusively triggered by proliferating HCASMC was tested using the biodegradable stent surface polymer poly-l-lactic acid (PLLA) and the MMP-9 cleavable peptide linkers named SRL and AVR. The specific peptide cleavage by MMP-9 was verified by attachment of the model compound fluorescein. Fluorescein release was observed in the presence of MMP-9 secreting HCASMC but not of proliferating HCAEC. Our findings suggest that cytotoxic drug conjugated polymers can be designed to selectively release the attached compound triggered by MMP-9 secreting smooth muscle cells. This novel concept may be beneficial for stent endothelialization thereby reducing the risk of restenosis and thrombosis.

Sirolimus-eluting stents for treatment of drug-eluting versus bare-metal stents restenosis: 42-month clinical outcomes from a Chinese single center.

BACKGROUND: Restenosis of bare-metal stents (BMS) and drug-eluting stents (DES) has been increasingly treated with sirolimus-eluting stents (SES), but the long-term outcomes are unknown. METHODS: In our study, 388 consecutive patients (144 DES restenosis and 244 BMS restenosis) with 400 lesions (147 DES restenosis and 253 BMS restenosis) treated with SES were included. The rates of target lesion revascularization (TLR) and major adverse cardiac events (MACE) at 42 months were analyzed. RESULTS: At the mean follow-up of 42 months, the rates of death (3.5% vs. 3.3%, P = 1.000) and myocardial infarction (2.8% vs. 1.2%, P = 0.431) in the DES group and BMS group were comparable. Compared with the BMS group, ischemia-driven TLR occurred with a higher frequency in the DES group (18.8% vs. 10.7%, P = 0.024). This translated into an increased rate of MACE in the DES group (22.2% vs. 14.0%, P = 0.034). Stent thrombosis occurred with a similar frequency in both groups (2.8% vs. 1.6%, P = 0.475). Multivariate analysis showed that DES restenosis (OR = 1.907, 95%CI 1.108 - 3.285, P = 0.020) and smoking (OR = 2.069; 95%CI 1.188 - 3.605; P = 0.010) were independent predictors of MACE. CONCLUSIONS: Although SES implantation appears to be safe and effective, it was associated with higher TLR recurrence for DES than BMS restenosis.

Early failure of coronary artery bypass grafts: an albumin cross-linked glutaraldehyde (BioGlue) related complication.

Bioglue which constitutes albumin cross linked with glutaraldehyde (ACLG) produced by Cryolife, Inc, Kennesaw, GA was introduced as a better alternative to GRF glue with less tissue necrosis. We report a case of a 69-year-old male who developed stenosis of his saphenous vein and internal thoracic artery bypass grafts, requiring re-do coronary artery bypass grafting. Both fibrotic narrowing were in close proximity to the site of Bioglue application and appears to be a reaction to the glue. The advent of ACLG has facilitated surgery; however, this case highlights a potential side effect, emphasizing the judicious use of this hemostatic agent in patients.

Paclitaxel-induced arterial wall toxicity and inflammation: part 2--long-term tissue response in a minipig model.

PURPOSE: In part 1 of the present study, the authors demonstrated that coronary paclitaxel uptake from drug eluting stents (DESs) was not dependent on exposure time and dose. In this second part, the effect of the different paclitaxel dose densities on long-term biologic behavior was evaluated. MATERIALS AND METHODS: In 40 minipigs, (with 4- and 12-week follow-up), identical stents with the same three paclitaxel dose densities as in part 1 were implanted in the right coronary artery. Minipigs implanted with Polyzene-F nanocoated stents served as the control group. Quantitative angiography measuring average luminal diameter (from three in-stent reference points), minimal luminal diameter (from the point of maximum in-stent stenosis), average late loss, maximum late loss, and binary stenosis rate was performed, as was microscopy to determine neointimal thickening, injury score, and inflammation. RESULTS: All three DESs were associated with a high average late loss, binary stenosis rate, and neointimal thickening, without significant differences. Drug-free stents had significantly less late in-stent stenosis: there was an average late loss of 0.3 mm +/- 0.3 in drug-free stents versus 0.8 mm +/- 0.2 in intermediate-dose stents and 1.5 mm +/- 0.6 in high-dose stents (P = .04). DES-associated inflammation was high in all DESs and six times higher as in the drug-free stents (Kornowski scores of 0.2 +/- 0.1 in drug-free stents, 1.3 +/- 0.9 in low-dose stents, 1.7 +/- 0.8 in intermediate-dose stents, and 1.3 +/- 1.0 in high-dose stents; P = .04). It worsened with time in all DESs, as did late in-stent stenosis. CONCLUSIONS: The extensive and long-term retention of paclitaxel even in a low-dose formulation, at least according to the present labeling of DESs, might be associated with negative long-term results with regard to inflammation and late in-stent stenosis.

[Drug-eluting stents: implications for modern coronary revascularization]. / Drug-eluting Stents : Implikationen für die moderne Koronarrevaskularisation.

Despite considerable data and years of experience in the field of coronary interventions and coronary surgery existing guidelines, which are still valid in the era of drug-eluting stents (DES), are often not followed. An increasing number of patients are treated with DES implantations against current recommendations. Due to antiplatelet therapy this impedes the planning and execution of additional invasive procedures that might be necessary after DES implantation and results in higher risks, if delaying treatment is not possible. As alternatives to stent implantation, coronary surgery nowadays offers a full range of individual treatment options which are highly effective and durable. They can be performed at low risk and do not interfere with subsequent invasive therapies. Patients suffering from relevant coronary artery disease and who are in need of additional invasive treatment should be considered for coronary surgery rather than stent implantation. If current guidelines are followed more closely, DES implantations and their accompanying drawbacks could be significantly reduced.

[Patients with coronary artery stents: when and how should operations be carried out?]. / Der Patient mit Koronarstent : Wann und wie sollte operiert werden?

Nowadays stents are implanted in over 90% of percutaneous coronary interventions. Depending on the type of stent implanted, dual antiplatelet therapy combining a cyclooxygenase inhibitor such as acetylsalicylic acid and an adenosine diphosphate receptor antagonist (thienopyridine) such as clopidogrel is required for 1-12 months. Premature termination of antiplatelet therapy during non-cardiac surgery significantly increases the risk of stent thrombosis and consequently myocardial infarction, whereas continuation of dual antiplatelet therapy during surgery increases the risk of severe bleeding. Accordingly, treatment recommendations have to be based on the individual relative risk. In cases with a high risk for major bleeding during surgery, interruption of antiplatelet therapy may be required, whereas in cases of a high risk of stent thrombosis, both antiplatelet drugs should be continued throughout surgery. Patients on dual antiplatelet therapy should be counseled by a team of anesthesiologists, surgeons and cardiologists, to devise the right point in time for the operation, the best perioperative antiplatelet therapy and the appropriate perioperative monitoring.

[Drug-eluting stents: implications for surgery patients]. / Drug-eluting Stents : Auswirkungen für chirurgische Patienten.

Percutaneous coronary intervention (PCI) has a special role in the treatment of coronary heart disease. The insertion of drug-eluting stents (DES) requires dual anti-platelet therapy for at least 1 year which makes planned and emergency surgery difficult. There is a dilemma between high risk of stent thrombosis and perioperative bleeding. There is no evidence-based, bridging therapy option available perioperatively. This complex of problems should be considered whenever PCI is performed. An interdisciplinary approach is obligatory in these imminent conditions to proceed with either interventional or surgical revascularization. Co-existing malignancies and disorders which must be treated surgically should be excluded before PCI. Furthermore, DES and dual anti-platelet therapy produce unanswered forensic questions. On legal grounds it is not possible to proceed with surgery in cases of medication with anti-platelet therapy. Therefore, it is mandatory to discuss the possible answers to this problem with health care lawyers. The patient must be informed about this complex of problems.

[Perioperative discontinuation of antiplatelet therapy of patients with coronary stents. Reevaluating the risks]. / Perioperatives Pausieren der antithrombozytären Therapie bei Patienten mit koronaren Stents : Ein neu zu bewertendes Risiko?

According to the present guidelines, patients with coronary stents are to be treated with dual antiplatelet therapy. In case surgery is needed, the risk of a fatal stent thrombosis by withdrawing antithrombotics needs to be balanced in each individual case against the risk of haemorrhagic complications on continued antiplatelet medication. We present a case of fatal stent thrombosis and discuss the current evidence regarding perioperative continuation and interruption of antiplatelet therapy for this patient population. In summary the haemorrhagic risk with acetylsalicylic acid for secondary prevention seems very low, and it should be discontinued only in selected cases. Continued dual anticoagulation concepts are also discussed.

Endothelialization of sirolimus-eluting stents with slow and extended drug release in the porcine overstretch model.

BACKGROUND: Vascular healing of intracoronary stents has been shown to be delayed in drug-eluting stents (DES) due to the cytotoxic compounds on the stent surface that prevent stent ingrowth and endothelialization. The lack of endothelialization explains the occurrence of late and very late stent thrombosis in DES. MATERIALS AND METHODS: In 11 house swines (body weight 38-45 kg), 3 stents were implanted randomly into the 3 large epicardial coronary arteries, namely a bare-metal stent (BMS), a sirolimus-eluting stent with slow-release (SES) and a SES with extended-release (SESXR). Stent length was 18 mm, and stent diameter 3 mm. All stents were of identical design. Animals were followed for 3 (n = 3), 7 (n = 4) and 14 (n = 4) days, respectively. One animal died before implantation due to hyperthermia. On the day of explantation, the animals were euthanized and endothelialization was tested by scanning electron microscopy after drying and sputtering the samples. Endothelial coverage was determined semiquantitatively by 2 observers. RESULTS: Endothelialization was more rapid with BMS and SESXR than SES at 3 and 14 days. At 7 days there were no significant differences between the 2 SES. CONCLUSIONS: Endothelialization of intracoronary stents is faster with BMS and SESXR at 3 days than with SES. These differences persist at 14 days, suggesting delayed vascular healing with the slow-release SES.

Comparison of sarpogrelate and ticlopidine in bare metal coronary stent implantation.

BACKGROUND: The efficacy and safety of sarpogrelate, a selective 5-hydroxytryptamine receptor subtype 2A antagonist, have not yet been established in bare metal coronary stenting. Accordingly, we sought to clarify whether treatment with sarpogrelate is clinically useful in bare metal coronary stenting. METHODS: A total of 450 patients who underwent successfully planned or unplanned bare metal coronary stenting were randomly divided into the following 2 groups: the sarpogrelate (300 mg/day) plus aspirin (100 mg/day) group (group S, n=225) and the ticlopidine (200 mg/day) plus aspirin (100 mg/day) group (group T, n=225). Either sarpogrelate or ticlopidine was administered for at least 4 weeks after the procedure. Follow-up coronary arteriography was performed at 6 months after the procedure. The primary endpoints were the incidence of adverse drug reactions requiring a withdrawal of treatment and the rate of binary restenosis. The secondary endpoint was the incidence of stent thrombosis. RESULTS: The incidence of adverse drug reactions requiring a withdrawal of treatment was significantly lower in group S than in group T (0.44% vs 8%, p=0.002). The rate of binary restenosis did not differ significantly between groups S and T (16.9% vs 18.2%). In addition, the incidence of subacute stent thrombosis did not differ between groups S and T (0.44% vs 0.44%). CONCLUSIONS: The incidence of adverse drug reactions requiring a withdrawal of treatment was significantly lower with sarpogrelate use than with ticlopidine use. The rate of binary restenosis and the incidence of subacute stent thrombosis did not differ between both drug groups.