Christos Pappas

Transulnar Compared With Transradial Artery Approach as a Default Strategy for Coronary Procedures A Randomized Trial The Transulnar or Transradial Instead of Coronary Transfemoral Angiographies Study (The AURA of ARTEMIS Study)

Background—The ulnar artery is rarely selected for coronary angiography or percutaneous coronary intervention despite the expanding use of the transradial approach. We aimed to establish noninferiority of a default transulnar relative to transradial approach in terms of feasibility and safety. Methods and Results—This was a prospective, randomized, multicenter, parallel-group study involving 902 patients at 5 sites eligible to undergo diagnostic coronary angiography and percutaneous coronary intervention. Patients were randomized in a 1:1 ratio to either transradial approach (reference intervention) or transulnar approach (experimental intervention) regardless of the Allen test results. The primary end point was a composite of cross-over to another arterial access, major adverse cardiovascular events, and major vascular events of the arm at 60 days. The study was prematurely terminated after the first interim analysis because of inferiority of the transulnar approach. Although the difference in the primary end point became inconclusive after adjustment for operator clustering (24.30%; 99.99% confidence interval [CI], −7.98% to 56.58%; P=0.03 at &agr;=0.0001), need for cross-over in the transulnar group remained inferior to transradial access site with a difference of 26.34% (95% CI, 11.96%–40.69%; P=0.004). Conclusions—As a result of higher cross-over rates, a first-line transulnar strategy was proven inferior to the transradial approach for coronary procedures. At present, the transulnar route should not be regarded as an acceptable alternative to the transradial access site. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01364532.

Communication network design using Particle Swarm Optimization

Particle swarm optimization is applied on an instance of single and mufti criteria network design problem. The primary goal of this study is to present the efficiency of a simple hybrid particle swarm optimization algorithm on the design of a network infrastructure including decisions concerning the locations and sizes of links. A complementary goal is to also address quality of service issues in the design process. Optimization objectives in this case are the network layout cost and the average packet delay in the network. Therefore a multi-objective instance of the hybrid PSO algorithm is applied. The particular hybrid PSO includes mutation to avoid premature convergence. For the same reason repulsion/attraction mechanisms are also applied on the single objective case. Mutation is passed on to the mufti-objective instance of the algorithm. Obtained results are compared with corresponding evolutionary approaches.

Model-driven development of composite web applications

As the number of available web services increases, the development of web applications that integrate existing web services becomes more and more popular. This class of web applications can be seen as the composition of web services around a user interface flow. In this paper, the application of model-driven techniques for the development of such user-centric web applications is presented. An approach for the modeling of the application using UML class and state transition diagrams and the transformation to appropriate platform specific code is presented. The service design is based on the introduced UML profiles, whereas on code level frameworks implementing the Model-View-Controller architectural pattern are targeted.

Supporting End-to-End Resource Virtualization for Web 2.0 Applications Using Service Oriented Architecture

In recent years, technologies have been introduced offering a large amount of computing and networking resources. New applications such as Google AdSense and BitTorrent can profit from the use of these resources. An efficient way of discovering and reserving these resources is by using the Service Oriented Architecture (SOA) concept. SOA can be considered as a philosophy or paradigm in organizing and utilizing services and capabilities that may be under the control of different ownership domains. This paper presents an architecture that can be used to support end-to-end resource virtualization for Web 2.0 applications and in particular for peer-to-peer applications by using the Service Oriented Architecture concept.

Design and Assessment of a Reputation-Based Trust Framework in Wireless Testbeds Utilizing User Experience

In this paper a novel Trust and User Experience Framework (TUEF) that enables trustworthiness between users and testbeds is proposed. The proposed framework utilizes: (1) monitoring data from testbeds and (2) user experience data, stemming from users’ capability to provide feedback regarding their Quality of Experience (QoE) and service received. The applicability of the TUEF is demonstrated in a wireless testbed environment as a proof-of-concept implementation, while the performance evaluation is based on both real and simulated experiments. The results presented in this paper demonstrate that the proposed trust mechanism succeeds in delivering accurate reputation values even in the case where a large number of malicious users may provide false feedback.

Particle swarm optimization for the multi level capacitated minimum spanning tree

In the presented study Particle Swarm Optimization will be applied on an instance of the Multi Level Capacitated Minimum Spanning Tree Problem. Specifically a diversity preservation global variant of the PSO meta-heuristic will be presented. The particular PSO variant includes Gaussian mutation to avoid premature convergence and alternative selection of the flight guide per particle. Obtained results are compared with corresponding evolutionary approaches. Potential tree solutions are encoded/decoded using Network Random Keys. A real world network design case is introduced.

Response to: Ticagrelor recommended over clopidogrel, only in clinical trials or also in a real-world practice?

We would like to thank Lombardi and colleagues for their interest on our article on ticagrelor recommended over clopidogrel in ST segment elevation myocardial infarction (STEMI) patients [1]. Authors questioned whether ticagrelor should be recommended over clopidogrel based on results of clinical trials only or also in a real-world practice [2]. They made their hypothesis based mainly on the occasional need for ticagrelor discontinuation due to dyspnea. It is well accepted that randomized controlled trials are the gold standard for novel therapies, although with inherent limitations. We also entirely agree with authors’ position about the additive value of real-life data. In PLATO trial, ticagrelor discontinuation rate due to dyspnea was indeed very rare at 0.9%. Data on dyspnea occurrence in acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI) and treated with P2Y12 receptor antagonists outside randomized trials are scarce, originating from small series with shortor medium-term follow-up and not specific for STEMI patients, for whom we dealt with in our review. We share authors concern that dyspnea rate may be higher in real life among ticagrelor users. However, referral to a case of ticagrelor discontinuation published by the authors is supportive of the relatively rareness of ticagrelor-attributed severe dyspnea, leading to its discontinuation. Nevertheless, in ‘reallife’ patients, we have recently reported for ticagrelor a worse compared to thienopyridine-treated patients’ nonpersistence rate, driven by a higher rate of switching, while cessation rates remain similar among P2Y12 receptor antagonists users; dyspnea was a common reason leading to switching from ticagrelor to a thienopyridine [3]. Up to the publication of our review, ‘real-life’ data outside clinical trials supporting of the superior effectiveness of ticagrelor over clopidogrel were indeed missing. However, in a very recent report from the Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies registry, among 45,073 myocardial infarction patients, the cumulative probability of the combined outcome of death, myocardial infarction, and stroke at 24 months was 11.7% (95% CI 10.6–12.8) with ticagrelor and 22.3% (95% CI 21.8–22.7) with clopidogrel [4]. Re-admissions with bleeding and PCI-related in-hospital bleeding events were more common among ticagrelor users. Unfortunately, data on ticagrelor intolerance or dyspnea attributed to ticagrelor or leading to discontinuation have not been provided. Importantly, this largest so far evaluation of clinical outcomes of ticagrelor and clopidogrel outside clinical trials provides overwhelming evidence that real-world outcomes in patients with a myocardial infarction treated with ticagrelor vs. clopidogrel appears similar to the benefit achieved in the PLATO trial.

Ticagrelor recommended over clopidogrel in STEMI patients

Patients with ST segment elevation myocardial infarction (STEMI) pose a special challenge for the clinician, as the optimal reperfusion therapy consisting of primary percutaneous coronary intervention (PCI), should be offered urgently, as soon as possible after first medical contact. As platelet activation has a central role in thrombus formation, particularly in the very early hours of STEMI [1], reaching adequate platelet inhibition at the time of primary PCI is considered a therapeutic strategy of utmost importance. Clopidogrel is a thienopyridine, which on top of aspirin, has been extensively used for almost two decades in patients undergoing a PCI, including those with STEMI. However, an impaired bioavailability following a 600 mg of this P2Y12 receptor antagonist loading dose (LD) has been described in STEMI patients. Plasma concentrations (Cmax) of unchanged clopidogrel, its inactive carboxyl metabolite and its active thiol metabolite have been found to be significantly lower in STEMI patients as compared to controls [2]. Time-tomaximum concentrations (Tmax in minutes) for unchanged clopidogrel, its inactive carboxyl metabolite and the active thiol metabolite were prolonged in STEMI patients as compared to controls:156 ± 110, 171 ± 108, 137 ± 100 vs. 84 ± 40, 93 ± 55, 55 ± 32, with p = .067, p = .023 and p = .05, respectively. The pharmacodynamic response to clopidogrel was also diminished in the STEMI group, with Δaggregation being 7 ± 8% for 5 μmol/L ADP and 6 ± 7% for 20 μmol/L ADP (at 4 h) and 25 ± 6% for 5 μmol/L ADP and 23 ± 9% for 20 μmol/L ADP (at 24 h). In contrast, in healthy volunteers at 6 h post LD Δaggregation was 56 ± 13% for 5 μmol/L ADP and 45 ± 25% for 20 μmol/L ADP. In another pharmacodynamic study 2-h post clopidogrel 600 mg loading, almost 2/3 of STEMI patients presented with increased platelet reactivity, defined as PRU ≥ 235 P2Y12 reaction units by the VerifyNow assay [3]. Compared to clopidogrel, ticagrelor – a cyclotriazolopyrimidine is a P2Y12 receptor antagonist, which provides stronger, faster and more consistent platelet inhibition [4,5]. Unlike clopidogrel, ticagrelor is not a prodrug and does not require metabolic activation to pursue its antiplatelet activity. In healthy subjects, it is rapidly absorbed, with a median time to peak concentration of 2–3 h. Ticagrelor and its active metabolite, AR-C124910XX, exhibit predictable linear pharmacokinetics in patients with stable coronary artery disease (CAD) and acute coronary syndrome (ACS) but this is not reflective of the physiological state of STEMI in which drug handling is invariably altered. In the STEMI cohort of the PLATelet inhibition and patient Outcomes (PLATO) trial, the reduction of the composite primary end point (death from vascular causes, myocardial infarction, or stroke) with ticagrelor versus clopidogrel [9.4% vs. 10.8%, with hazard ratio (HR) 0.87, 95% confidence interval (CI), 0.75–1.01, and p = .07] was consistent with the overall trial results. The favorable effects of ticagrelor over clopidogrel, were consistent regardless of gender (p for interaction = .98), age group (younger or older than 65 years, p for interaction = .84) or the presence of diabetes (p for interaction = .91) [6]. Furthermore, ticagrelor reduced several secondary end points, including myocardial infarction alone (HR 0.80, 95% CI 0.65–0.98) and total mortality (HR 0.82, 95% CI 0.71–0.96). No increase in the risk of major bleeding (HR 0.98, 95%CI 0.79–1.22) in the ticagrelor treated patients reported, compared with clopidogrel. Following the above results, European Society of Cardiology STEMI guidelines suggest the use of ticagrelor as early as possible with a class I (level of evidence B) recommendation, and the use of clopidogrel with a class I (level of evidence C) recommendation, preferably when prasugrel or ticagrelor are either not available or contraindicated [7]. In contrast, in the American College of Cardiology/American Heart Association STEMI guidelines both ticagrelor and clopidogrel are recommendedas early as possible or at timeof PCIwith a class I (level of evidence B) recommendation [8]. A clinician deciding over the use of ticagrelor or clopidogrel should carefully consider contraindications and special warning and precaution for its drug. Ticagrelor is contraindicated in the presence of prior intracranial hemorrhage or moderate/ severe hepatic impairment, while there is a warning and precaution for its use if there is a history of asthma/chronic obstructive pulmonary disease, hyperuricemia or gouty arthritis, an increased risk of bradycardiac events or cotreatment with strong CYP3A4 inducers. End-stage renal failure requiring hemodialysis needs special attention for both ticagrelor and clopidogrel. Conditions and comedication related to increased bleeding risk are also common for ticagrelor and clopidogrel, although in ‘real life’, in their presence, the less potent clopidogrel is preferred [9]. Cotreatment with moderate/strong CYP2C19 inhibitors requires special attention for clopidogrel administration.

Heuristics for the multi-level capacitated minimum spanning tree problem

The capacitated minimum spanning tree (CMST) problem is fundamental to the design of centralized communication networks. In this paper we consider the multi-level capacitated minimum spanning tree problem, a generalization of the well-known CMST problem. Based on work previously done in the field, three heuristics are presented, addressing unit and non-unit demand cases. The proposed heuristics have been also integrated into a mixed integer programming solver. Evaluation results are presented, for an extensive set of experiments, indicating the improvements that the heuristics bring to the particular problem.

Cangrelor in Ticagrelor-Loaded STEMI Patients Undergoing Primary Percutaneous Coronary Intervention

The intravenous P2Y12 receptor antagonist cangrelor provides rapid onset and offset of platelet inhibition [(1)][1]. Compared with clopidogrel, cangrelor has significantly reduced the rate of ischemic events, including stent thrombosis, during percutaneous coronary intervention (PCI), with no