Association of interleukin 6 -174 G/C polymorphism with coronary artery disease and circulating IL-6 levels: a systematic review and meta-analysis

Introduction: Circulating IL-6 levels and at least one polymorphic form of IL6 gene (IL6 -174 G/C, rs1800795) have been shown to be independently associated with coronary artery disease (CAD) by several investigators. Despite more than 12 published meta-analyses on this subject, association of -174 G/C with CAD, especially amongst distinct ancestral population groups remain unclear. We, therefore, conducted a systematic review and an updated meta-analysis to comprehensively ascertain the association of IL6 -174 G/C with CAD and circulating IL-6 levels. Materials and methods: Relevant case-control/cohort studies investigating association of -174 G/C with CAD and circulating IL-6 levels were identified following a comprehensive online search. Association status for CAD was determined for the pooled sample, as well as separately for major ancestral subgroups. Association status for circulating IL-6 levels was assessed for the pooled sample, as well as separately for CAD cases and CAD free controls. Study-level odds ratios (OR) and 95% confidence intervals (CI) were pooled using random/fixed-effects model. Results: Quantitative synthesis for the CAD endpoint was performed using 55 separate qualifying studies with a collective sample size of 51,213 (19,160 cases/32,053 controls). Pooled association of -174 G/C with CAD was found to be statistically significant through dominant (OR 1.15; 95% CI 1.05-1.25, p = 0.002) as well as allelic genetic model comparisons (OR 1.13, 95% CI 1.06-1.21, p = 0.0003). This effect was largely driven by Asian and Asian Indian ancestral subgroups, which also showed significant association with CAD in both genetic model comparisons (OR range 1.29-1.53, p value range ≤ 0.02). Other ancestral subgroups failed to show any meaningful association. Circulating IL-6 levels were found to be significantly higher amongst the 'C' allele carriers in the pooled sample (Standard mean difference, SMD 0.11, 95% CI 0.01-0.22 pg/ml, p = 0.009) as well as in the CAD free control subgroup (SMD 0.10, 95% CI 0.02-0.17 pg/ml, p = 0.009), though not in the CAD case subgroup (SMD 0.17, 95% CI = - 0.02 to 0.37, p = 0.12). Conclusions: The present systematic review and meta-analysis demonstrate an overall association between IL6 -174 G/C polymorphism and CAD, which seems to be mainly driven by Asian and Asian Indian ancestral subgroups. Upregulation of plasma IL-6 levels in the 'C' allele carriers seems to be at least partly responsible for this observed association. This warrants further investigations with large, structured case-control studies especially amongst Asian and Asian Indian ancestral groups.</p

Antithrombotic therapy with or without aspirin after percutaneous coronary intervention or acute coronary syndrome in patients taking oral anticoagulation: a meta-analysis and network analysis of randomized controlled trials

Introduction: Trials investigating aspirin omission in patients taking oral anticoagulation (OAC) after percutaneous coronary intervention (PCI) or acute coronary syndrome (ACS) were not powered to assess rates of major bleeding or ischemic events.Methods: We performed an updated meta-analysis and network analysis of randomized trials comparing treatment with or without aspirin in patients taking OAC and a P2Y12-inhibitor after PCI or ACS. The primary outcome was TIMI major bleeding.Results: Five trials enrolling 11,542 patients allocated to antithrombotic regimens omitting (n = 5795) or including aspirin (n = 5747) were included. Aspirin omission was associated with a lower risk of TIMI major bleeding (RR = 0.56, 95% CI [0.44-0.71]; P Conclusions: In patients taking OAC after PCI or ACS, aspirin omission is associated with a lower risk of TIMI major bleeding, with a numerically increased risk of MI, which is statistically significant when only NOAC-based trials are considered. This supports individualization of the treatment regimen based on patient risk.</p

Sex-specific inequalities in the treatment of severely calcified coronary lesions: a sub-analysis of the PREPARE-CALC trial

Background: Coronary vessels in women may have anatomical and histological particularities. The aim of this study was to investigate sex-specific characteristics and outcomes of patients with calcified coronary arteries in the Prepare-CALC (Comparison of Strategies to Prepare Severely Calcified Coronary Lesions) trial.  Methods: The Prepare-CALC trial randomised patients with severe coronary calcification to coronary lesion preparation either using modified balloons (MB; cutting or scoring) or rotational atherectomy (RA).  Results: Of 200 randomised patients, 24% were women. Strategy success in general was similar between women (93.8%) and men (88.2%; p=0.27). For men, strategy success was significantly more common with an RA-based strategy than an MB-based strategy (98.7% in the RA group versus 77.3% in the MB group, p0.99, p for interaction between sex and treatment strategy=0.03). Overall, significant complications such as death, MI, stent thrombosis, bypass operation and perforations were rare and did not differ significantly by gender or treatment strategy. Plaque rupture and disrupted calcified nodules were more common in women.  Conclusion: In a well-defined patient population with severely calcified coronary arteries, lesion preparation with an RA-strategy was superior to an MB-strategy in men. For women, both RA and MB strategies appear to have a similar success rate, although definitive conclusions are limited due to the small number of women in the trial. </p

A prospective trial of a novel low-dose paclitaxel-coated balloon therapy in patients with restenosis in drug-eluting coronary stents Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-stent REstenosis 3A (ISAR-DESIRE 3A)

Objectives: We investigated the clinical efficacy of a paclitaxel-coated balloon (PCB) with a novel matrix coating and reduced drug concentration in comparison with a widely used PCB with iopromide excipient. Methods: We prospectively enrolled patients with restenosis in drug-eluting stents. All patients were treated with a novel low-dose PCB with citrate-based excipient (Agent PCB). Angiographic follow-up was scheduled at 6-8 months. Outcomes were compared against those of patients treated with iopromide excipient PCB (SeQuent Please PCB) enrolled in a trial with identical inclusion and exclusion criteria. The primary endpoint was percent diameter stenosis (%DS) at follow-up angiography. The primary hypothesis was that the investigational device would be non-inferior to the control device (ClinicalTrials.gov Identifier: NCT02367495). Results: One hundred twenty-five patients with 151 lesions were enrolled. Mean age was 68.1 ± 10.2 years, 40.8% had diabetes mellitus and 80.1% had focal morphology in-stent restenosis. Follow-up angiography data at 6-8 months was available for 102 (81.6%) patients. The Agent PCB was non-inferior to the SeQuent Please PCB in terms of the primary endpoint (38.9 ± 17.5 vs. 38.1 ± 21.5%; p non-inferiority = 0.0056). Late lumen loss was also comparable between the groups (0.35 ± 0.55 vs. 0.37 ± 0.59; p = 0.71). There was no difference between the groups in the incidence of TLR (27.7% vs. 22.1%; p = 0.31), death or myocardial infarction (4.2% vs. 4.4%; p = 0.92) or target lesion thrombosis (1.0% vs. 0.7%; p = 0.93). Conclusion: In patients with DES restenosis, angioplasty with a novel PCB with citrate-based excipient was non-inferior to PCB with iopromide excipient in terms of angiographic outcome.</p

Standardized Minimalistic Transfemoral Transcatheter Aortic Valve Replacement (TAVR) Using the SAPIEN 3 Device: Stepwise Description, Feasibility, and Safety from a Large Consecutive Single-Center Single-Operator Cohort

<p><b>Background:</b> To describe our updated minimalist approach (MA) for transfemoral transcatheter aortic valve replacement (TF-TAVR) using the SAPIEN 3 device and its evolution, as well as associated safety and efficacy parameters from a large cohort of patients.</p> <p><b>Methods:</b> A stepwise description of the MA technique for TAVR for 300 consecutive patients was detailed. Safety and efficacy parameters were assessed using the VARC-2 criteria at the in-hospital and 30-days follow-up.</p> <p><b>Results:</b> A total of 300 consecutive patients (80 ± 7 years; median Logistic EuroSCORE of 11.4% [7.5–17.8]) between January 2014 and May 2016 were evaluated. TF-TAVR was performed under conscious sedation in 247 (82%) patients. Device success was achieved in 286 (95.6%) patients, and intended prosthesis performance in 289 (96.3%) patients. Significant paravalvular leak (PVL) graded more than mild was noted in 7 (2%) patients. No patient had severe PVL. All-cause mortality was noted in one (0.3%) patient in-hospital and in 2 (0.7%) patients at the 30-days follow-up. Major stroke occurred in 4 (1.3%) patients. 9 (3%) patients had major vascular complications at 30-days follow up. MACCE (VARC-2 criteria) were observed in 21 (7%) in-hospital and 25 (8.3%) at 30 days. A new permanent pacemaker implantation was required in 29 (10.7%) patients, and was reduced from 18% to 5.6% (<i>p</i> = 0.001) in a subgroup analysis considering higher implantation position of the valve after the first year of experience.</p> <p><b>Conclusion:</b> MA of TF-TAVR, when simplified and standardized, is reproducible, safe and efficient, and should be encouraged to be accepted as the standard method of care.</p

Angiographic performance of everolimus-eluting stents for the treatment of coronary in-stent restenosis in daily practice

Objectives: The present study aims to analyze the angiographic anti-restenotic performance of durable polymer everolimus-eluting stents (EES) for the treatment of in-stent restenosis (ISR) in daily practice.Background: Randomized data is available supporting the use of drug-coated balloons and drug-eluting stents for the treatment of ISR; however, additional real-world data including angiographic follow-up is needed.Methods: Patients who underwent EES-implantation for the treatment of drug-eluting stent ISR and attended for a 6–8 months angiographic surveillance were analyzed. Off-line assessment of the angiograms was conducted at a central quantitative coronary angiographic core laboratory. Results: A total of 426 patients with ISR were treated with EES and had undergone angiographic follow-up. The mean age was 66.8 ± 9.9 years and 27.5% suffered from diabetes. A total of 459 lesions were treated. The diameter stenosis decreased from 64.3 ± 19.1% (preprocedural) to 12.0 ± 6.4% (postprocedural). At 6–8 months angiographic follow-up, the in-segment diameter stenosis was 38.3 ± 21.7% and the in-stent late luminal loss was 0.54 ± 0.74 mm in the treated area analysis. The rate of recurrent binary restenosis was 25.7%.Conclusions: In the setting of ISR, the angiographic anti-restenotic efficacy of stenting with EES is comparable to that observed in randomized clinical trials and less favorable than its performance in patients undergoing stenting for de novo disease.</div

Pathway Analysis Using Genome-Wide Association Study Data for Coronary Restenosis – A Potential Role for the PARVB Gene

<div><p>Background</p><p>Coronary restenosis after percutaneous coronary intervention (PCI) still remains a significant limitation of the procedure. The causative mechanisms of restenosis have not yet been fully identified. The goal of the current study was to perform gene-set analysis of biological pathways related to inflammation, proliferation, vascular function and transcriptional regulation on coronary restenosis to identify novel genes and pathways related to this condition.</p><p>Methods</p><p>The GENetic DEterminants of Restenosis (GENDER) databank contains genotypic data of 556,099SNPs of 295 cases with restenosis and 571 matched controls. Fifty-four pathways, related to known restenosis-related processes, were selected. Gene-set analysis was performed using PLINK, GRASS and ALIGATOR software. Pathways with a p<0.01 were fine-mapped and significantly associated SNPs were analyzed in an independent replication cohort.</p><p>Results</p><p>Six pathways (cell-extracellular matrix (ECM) interactions pathway, IL2 signaling pathway, IL6 signaling pathway, platelet derived growth factor pathway, vitamin D receptor pathway and the mitochondria pathway) were significantly associated in one or two of the software packages. Two SNPs in the cell-ECM interactions pathway were replicated in an independent restenosis cohort. No replication was obtained for the other pathways.</p><p>Conclusion</p><p>With these results we demonstrate a potential role of the cell-ECM interactions pathway in the development of coronary restenosis. These findings contribute to the increasing knowledge of the genetic etiology of restenosis formation and could serve as a hypothesis-generating effort for further functional studies.</p></div

Design and rationale of a randomized trial of COBRA PzF stenting to REDUCE duration of triple therapy (COBRA-REDUCE)

Background/purpose: A coronary stent with thromboresistant and pro-healing properties such as the polymer polyzene F-coated (COBRA PzF) stent might safely allow for a very short duration of triple therapy in patients taking oral anticoagulation (OAC) who undergo coronary stenting.Methods: The COBRA-REDUCE trial is a prospective, multinational, randomized, open-label, assessor-blinded trial. A total of 996 patients at high bleeding risk because of requirement for OAC (with a vitamin K antagonist or non-vitamin K antagonist for any indication) will be randomized at sites in the United States and Europe to treatment with the COBRA-PzF stent followed by very short duration (14 days) DAPT or a Food and Drug Administration (FDA)-approved new generation drug-eluting stent followed by guideline-recommended DAPT duration (3 or 6 months). Two co-primary endpoints will be tested at 6 months: a bleeding co-primary endpoint (bleeding academic research consortium [BARC] ≥2 bleeding beyond 14 days or after hospital discharge, whichever is later [superiority hypothesis]) and a thrombo-embolic co-primary endpoint (the composite of all-cause death, myocardial infarction, definite/probable stent thrombosis or ischaemic stroke [non-inferiority hypothesis]). The trial is registered at clinicaltrials.gov (NCT02594501).Conclusion: The COBRA-REDUCE trial will determine whether coronary stenting with the COBRA PzF stent followed by 14 days of clopidogrel will reduce bleeding without increasing thrombo-embolic events compared with FDA-approved DES followed by 3-6 months clopidogrel in patients taking OAC and aspirin.</p

Pathways associated with restenosis with PLINK or GRASS.

<p>A complete overview of all pathways can be found in Supplementary <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0070676#pone.0070676.s001" target="_blank">Table S1</a>. NS, not significant (pathway did not meet test criteria).</p

10-Year outcomes from a randomized trial of polymer-free versus durable polymer drug-eluting coronary stents

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).</p