Updated evidence on intracoronary abciximab in ST-elevation myocardial infarction: A systematic review and meta-analysis of randomized clinical trials

Abstract Background: Intracoronary (IC) abciximab administration remains a promising approach aimed to increase a drug concentration in the target area and possibly improve clinical outcomes in the setting of ST-segment elevation myocardial infarction (STEMI). The goal of this literature review and meta-analysis is to update available knowledge comparing IC and intravenous (IV) abciximab administration in STEMI patients. Methods: A total of 7 randomized clinical trials (RCTs) with a median follow-up of 3 months were included in the meta-analysis (n = 3311). All-cause mortality was selected as the primary end point while recurrent myocardial infarction (re-MI), target vessel revascularization (TVR) and major bleeding complications were the secondary end points. Results: IC abciximab did not provide any benefits in terms of all-cause mortality as compared with IV abciximab (odds ratio [OR] 0.67; 95% confidence interval [CI] 0.34 1.34). However, this neutral effect was driven by the AIDA STEMI trial. The IC route was associated with a reduced rate of re-MI when compared with IV administration (OR 0.61; 95% CI 0.40 0.92) but the difference disappeared after one of the RCTs was excluded from the analysis. Both strategies were equal regarding TVR (OR 0.66; 95% CI 0.40 1.09) and major bleeding complications (OR 1.18; 95% CI 0.76 1.83). Conclusions: Our updated meta-analysis shows that the clinical superiority of IC over IV abciximab administration in STEMI patients is no longer clear after the release of the AIDA STEMI trial results. Further research in high-risk STEMI patients is warranted to finally determine clinical advantages of IC vs IV abciximab administration. (Cardiol J 2012; 19, 3:230 242

Order preserving pattern matching on trees and DAGs

The order preserving pattern matching (OPPM) problem is, given a pattern string $p$ and a text string $t$, find all substrings of $t$ which have the same relative orders as $p$. In this paper, we consider two variants of the OPPM problem where a set of text strings is given as a tree or a DAG. We show that the OPPM problem for a single pattern $p$ of length $m$ and a text tree $T$ of size $N$ can be solved in $O(m+N)$ time if the characters of $p$ are drawn from an integer alphabet of polynomial size. The time complexity becomes $O(m \log m + N)$ if the pattern $p$ is over a general ordered alphabet. We then show that the OPPM problem for a single pattern and a text DAG is NP-complete

Montessori's mediation of meaning: a social semiotic perspective

The distinctive objects designed by Dr Maria Montessori as the centrepiece of her approach to pedagogy are the topic of this study. The Montessori approach to pedagogy, celebrating its centenary in 2007, continues to be used in classrooms throughout the world. Despite such widespread and enduring use, there has been little analysis of the Montessori objects to evaluate or understand their pedagogic impact. This study begins by outlining the provenance of the Montessori objects, reaching the conclusion that the tendency to interpret them from the perspective of the progressive education movement of the early twentieth century fails to provide insights into the developmental potential embodied in the objects. In order to appreciate that potential more fully, the study explores the design of the objects, specifically, the way in which the semiotic qualities embodied in their design orient children to the meanings of educational knowledge. A meta-analytic framework comprising three components is used to analyse the semiotic potential of the Montessori objects as educational artefacts. First, Vygotsky’s model of development is used to analyse the objects as external mediational means and to recognise the objects as complexes of signs materialising educational knowledge. In order to understand how the objects capture, in the form of concrete analogues, the linguistic meanings which construe educational knowledge, systemic functional linguistics, the second component of the framework, is used to achieve a rich and detailed social semiotic analysis of these relations, in particular, material and linguistic representations of abstract educational meanings. Finally, the pedagogic device, a central feature of Bernstein’s sociology of pedagogy, is used to analyse how the Montessori objects re-contextualise educational knowledge as developmental pedagogy. Particular attention is paid to the Montessori literacy pedagogy, in which the study of grammar plays a central role. The study reveals a central design principle which distinguishes the Montessori objects. This principle is the redundant representation of educational knowledge across multiple semiotic modes. Each representation holds constant the underlying meaning relations which construe quanta of educational knowledge, giving children the freedom to engage with this knowledge playfully, independently and successfully. The conclusion drawn from this study is that the design of the Montessori objects represents valuable educational potential which deserves continued investigation, as well as wider recognition and application. To initiate this process, the findings in this study may provide insights which can be used to develop tools for evaluating and enhancing the implementation of Montessori pedagogy in Montessori schools. The findings may also be used to adapt Montessori design principles for the benefit of educators working in non-Montessori contexts, in particular, those educators concerned with developing pedagogies which promote equitable access to educational knowledge

Metabolism of ticagrelor in patients with acute coronary syndromes.

© The Author(s) 2018Ticagrelor is a state-of-the-art antiplatelet agent used for the treatment of patients with acute coronary syndromes (ACS). Unlike remaining oral P2Y12 receptor inhibitors ticagrelor does not require metabolic activation to exert its antiplatelet action. Still, ticagrelor is extensively metabolized by hepatic CYP3A enzymes, and AR-C124910XX is its only active metabolite. A post hoc analysis of patient-level (n = 117) pharmacokinetic data pooled from two prospective studies was performed to identify clinical characteristics affecting the degree of AR-C124910XX formation during the first six hours after 180 mg ticagrelor loading dose in the setting of ACS. Both linear and multiple regression analyses indicated that ACS patients presenting with ST-elevation myocardial infarction or suffering from diabetes mellitus are more likely to have decreased rate of ticagrelor metabolism during the acute phase of ACS. Administration of morphine during ACS was found to negatively influence transformation of ticagrelor into AR-C124910XX when assessed with linear regression analysis, but not with multiple regression analysis. On the other hand, smoking appears to increase the degree of ticagrelor transformation in ACS patients. Mechanisms underlying our findings and their clinical significance warrant further research.Peer reviewedFinal Published versio

Oral NAloxone to overcome the moRphine effect in acute COronary syndrome patients treated with TICagrelor — NARCOTIC trial

Background: Numerous worldwide clinical trials have proven the indisputably negative influence of morphine on the pharmacokinetics and pharmacodynamics of P2Y12 receptor inhibitors in patients presenting with acute coronary syndromes. The aim of this trial was to evaluate whether oral co-administration of an anti-opioid agent, naloxone, can be considered a successful approach to overcome ‘the morphine effect’. Methods: Consecutive unstable angina patients receiving ticagrelor and morphine with or without orally administered naloxone underwent assessment of platelet reactivity using Multiplate analyzer as well as evaluation of the pharmacokinetic profile of ticagrelor and its active metabolite, AR-C124910XX, at nine pre-defined time points within the first 6 hours following oral intake of the ticagrelor loading dose. Results: The trial shows no significant differences regarding the pharmacokinetics of ticagrelor between both study arms throughout the study period. AR-C124910XX plasma concentration was significantly higher 120 min after the ticagrelor loading dose administration (p = 0.0417). However, the evaluation of pharmacodynamics did not show any statistically significant differences between the study arms. Conclusions: To conclude, this trial shows that naloxone co-administration in ticagrelor-treated acute coronary syndrome patients on concomitant treatment with morphine shows no definite superiority in terms of ticagrelor pharmacokinetic and pharmacodynamic profile

Ischaemic and bleeding complications with new, compared to standard, ADP-antagonist regimens in acute coronary syndromes: a meta-analysis of randomized trials

Background: Platelets play a pivotal role in the pathogenesis of acute coronary syndromes (ACS) and their inhibition remains a mainstay therapy in this setting. We aimed to perform a meta-analysis of randomized trials to evaluate the benefits of new oral antiplatelet regimens to block platelet ADPreceptors compared to standard-dose clopidogrel (300 mg loading dose followed by 75 mg/daily). Methods: We obtained results from all randomized trials enrolling patients with ACS. Primary endpoint was mortality. Secondary endpoints were myocardial infarction and definite in-stent thrombosis. Safety endpoint was the risk of major bleeding complications. We prespecified subanalyses according to new antiplatelet drugs (prasugrel/ticagrelor), high-dose clopidogrel (600 mg) and patients undergoing percutaneous coronary intervention. Results: A total of seven randomized trials were finally included in the meta-analysis (n = 58 591). We observed a significant reduction in mortality (2.9% vs. 3.4%, OR= 0.87, 95% CI 0.79–0.95, P = 0.002), recurrent myocardial infarction (4.2% vs. 5.2%, OR= 0.80, 95% CI 0.74–0.87, P < 0.0001), definite in-stent thrombosis (0.9% vs. 1.7%, OR= 0.52, 95% CI 0.43–0.63, P < 0.0001). The benefits in mortality and reinfarction were driven by the treatment with prasugrel or ticagrelor, without a significant difference in terms of major bleeding complications as compared to standarddose clopidogrel (5% vs. 4.7%, OR= 1.06 95% CI 0.96–1.17, P = 0.25). Conclusions: This meta-analysis showed that new oral antiplatelet regimens are associated with a significant reduction in mortality, reinfarction and in-stent thrombosis in ACS patients without an overall increase of major bleeding when treated with new antiplatelet drugs

Impact of mild therapeutic hypothermia on bioavailability of ticagrelor in patients with acute myocardial infarction after out-of-hospital cardiac arrest

Background: Out-of-hospital cardiac arrest (OHCA) frequently occurs in the early phase of acute myocardial infarction (MI). Survivors require percutaneous coronary intervention (PCI) with concomitantdual antiplatelet therapy. Target temperature management, including mild therapeutic hypothermia (MTH), should be applied in comatose patients after resuscitation. However, an increased risk of stent thrombosis in patients undergoing hypothermia is observed. The aim of this study was to assess the impact of MTH on pharmacokinetics of ticagrelor in cardiac arrest survivors with MI treated with MTH and PCI.Methods: In a prospective, observational, single-center study pharmacokinetics of ticagrelor were evaluated in 41 MI patients, including 11 patients after OHCA undergoing MTH (MTH group) and 30 MI patients without OHCA and MTH (no-MTH group). Blood samples were drawn before administration of a 180 mg ticagrelor loading dose, and 30 min, 1, 2, 4, 6, 12, and 24 h after the loading dose.Results: In patients treated with MTH total exposure to ticagrelor during the first 12 h after the loading dose and maximal plasma concentration of ticagrelor were significantly lower than in the no-MTH group (AUC(0–12): 3403 ± 2879 vs. 8746 ± 5596 ng·h/mL, difference: 61%, p = 0.01; Cmax: 475 ± 353 vs. 1568 ± 784 ng/mL, p = 0.0002). Time to achieve maximal ticagrelor plasma concentration was also delayed in the MTH group (tmax for ticagrelor: 12 [6–24] vs. 4 [2–12] h, p = 0.01).Conclusions: Bioavailability of ticagrelor was substantially decreased and delayed in MI patients treated with MTH after OHCA. Trial registration: ClinicalTrials.gov Identifier: NCT0261193

Drug-coated balloons in treatment of in-stent restenosis: a meta-analysis of randomised controlled trials

Background Drug-coated balloons (DCBs) have been developed for the percutaneous treatment of coronary artery disease. An initial focus has been the management of in-stent restenosis (ISR) but randomised controlled trials (RCTs) have been small and powered only for angiographic endpoints. Objective The aim of the work was to assess the clinical and angiographic outcomes of patients treated for ISR with DCB versus control (balloon angioplasty or drug-eluting stents) by a meta-analysis of RCTs. Methods A comprehensive search was performed of RCTs where patients with ISR were randomly assigned to either DCB or alternative coronary intervention. Outcome measurements were death, myocardial infarction (MI), target lesion revascularisation (TLR), binary definition of restenosis and in-lesion late luminal loss (LLL). Results Four studies were identified that fulfilled the inclusion criteria. Pooled odds ratios (ORs) were calculated for patients treated for ISR (n = 399). Mean follow-up duration was 14.5 months. DCBs were associated with lower rates of TLR [8.8 vs. 29.7 % OR (95 % confidence interval, CI) 0.20 (0.11–0.36), p\0.0001], binary restenosis [10.3 vs. 41.3 % OR (95 % CI) 0.13 (0.07–0.24), p\0.00001] and MI [0.5 vs. 3.8 %, OR (95 % CI) 0.21 (0.04–1.00), p = 0.05]. No significant heterogeneity was identified. Conclusion Drug-coated balloons appear to be effective versus control in reducing TLR and possibly MI versus balloon angioplasty or drug-eluting stents in the management of ISR