Impact of extracardiac findings during cardiac MR on patient management and outcome.

BACKGROUND: Cardiac magnetic resonance (CMR) is increasingly used to assess heart diseases. Relevant non-cardiac diseases may also be incidentally found on CMR images. The aim of this study was to determine the prevalence and nature of incidental extra-cardiac findings (IEF) and their clinical impact in non-selected patients referred for CMR. MATERIAL/METHODS: MR images of 762 consecutive patients (515 men, age: 56±18 years) referred for CMR were prospectively interpreted by 2 radiologists blinded for any previous imaging study. IEFs were classified as major when requiring treatment, follow-up, or further investigation. Clinical follow-up was performed by checking hospital information records and by calling referring physicians. The 2 endpoints were: 1) non-cardiac death and new treatment related to major IEFs, and 2) hospitalization related to major IEFs during follow-up. RESULTS: Major IEFs were proven in 129 patients (18.6% of the study population), 14% of those being unknown before CMR. During 15±6 month follow-up, treatment of confirmed major IEFs was initiated in 1.4%, and no non-cardiac deaths occurred. Hospitalization occurred in 8 patients (1.0% of the study population) with confirmed major IEFs and none occurred in the remaining 110 patients with unconfirmed/unexplored major IEFs (p<0.001). CONCLUSIONS: Screening for major IEFs in a population referred for routine CMR changed management in 1.4% of patients. Major IEFs unknown before CMR but without further exploration, however, carried a favorable prognosis over a follow-up period of 15 months.

The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data.

BACKGROUND: Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings. METHODS: We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites. FINDINGS: We included 61 studies done between January, 1998, and December, 2012, and included 14 327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4-97·9) at day 28 and 96·0% (95·6-96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86-0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5-96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3-96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0·92, 95% CI 0·85-0·99; p=0·037 for every 1 mg/kg increase in total artemether dose). INTERPRETATION: The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups. FUNDING: Bill & Melinda Gates Foundation.

Implementing evidence-based patient and family education on oral anticoagulation therapy: a community-based participatory project.

AIMS AND OBJECTIVES: This study aimed at developing and implementing evidence-based patient and family education on oral anticoagulation therapy. BACKGROUND: The number of persons with chronic diseases who live at home is increasing. They have to manage multiple diseases and complex treatments. One such treatment is oral anticoagulation therapy, a high risk variable dose medication. Adherence to oral anticoagulation therapy is jeopardised by limited information about the medications, their risk and complications, the impact of individual daily routine and the limited inclusion of family members in education. Hence, improved and tailored education is essential for patients and families to manage oral anticoagulation therapy at home. DESIGN AND METHODS: A community-based participatory research design combined with the Precede-Proceed model was used including a systematic literature review, posteducation analysis, an online nurse survey, a documentation analysis and patient/family interviews. The study was conducted between April 2010-December 2012 at a department of general internal medicine in a teaching hospital in Switzerland. Participants were the department's nursing and medical professionals including the patients and their families. RESULTS: The evidence-based patient and family education on oral anticoagulation therapy emerged comprising a learning assessment, teaching units, clarification of responsibilities of nurse professionals and documentation guidelines. CONCLUSION AND CLINICAL RELEVANCE: The inclusion of the whole department has contributed to the development and implementation of this evidence-based patient family education on oral anticoagulation therapy, which encompasses local characteristics and patient preferences. This education is now being used throughout the department.

Méta-analyses d'essais randomisés sur données individuelles dans le traitement des cancers ORL non métastatiques : principes, résultats, perspectives [Individual patient data meta-analyses of randomized trials for the treatment of non-metastatic head and neck squamous cell carcinomas: Principles, results and perspectives].

Meta-analyses are considered as an important pillar of evidence-based medicine. The aim of this review is to describe the main principles of a meta-analysis and to use examples of head and neck oncology to demonstrate their clinical impact and methodological interest. The major role of individual patient data is outlined, as well as the superiority of individual patient data over meta-analyses based on published summary data. The major clinical breakthrough of head and neck meta-analyses are summarized, regarding concomitant chemotherapy, altered fractionated chemotherapy, new regimens of induction chemotherapy or the use of radioprotectants. Recent methodological developments are described, including network meta-analyses, the validation of surrogate markers. Lastly, the future of meta-analyses is discussed in the context of personalized medicine.

Glutamine and antioxidants in the critically ill patient: a post hoc analysis of a large-scale randomized trial.

BACKGROUND: The recent large randomized controlled trial of glutamine and antioxidant supplementation suggested that high-dose glutamine is associated with increased mortality in critically ill patients with multiorgan failure. The objectives of the present analyses were to reevaluate the effect of supplementation after controlling for baseline covariates and to identify potentially important subgroup effects. MATERIALS AND METHODS: This study was a post hoc analysis of a prospective factorial 2 × 2 randomized trial conducted in 40 intensive care units in North America and Europe. In total, 1223 mechanically ventilated adult patients with multiorgan failure were randomized to receive glutamine, antioxidants, both glutamine and antioxidants, or placebo administered separate from artificial nutrition. We compared each of the 3 active treatment arms (glutamine alone, antioxidants alone, and glutamine + antioxidants) with placebo on 28-day mortality. Post hoc, treatment effects were examined within subgroups defined by baseline patient characteristics. Logistic regression was used to estimate treatment effects within subgroups after adjustment for baseline covariates and to identify treatment-by-subgroup interactions (effect modification). RESULTS: The 28-day mortality rates in the placebo, glutamine, antioxidant, and combination arms were 25%, 32%, 29%, and 33%, respectively. After adjusting for prespecified baseline covariates, the adjusted odds ratio of 28-day mortality vs placebo was 1.5 (95% confidence interval, 1.0-2.1, P = .05), 1.2 (0.8-1.8, P = .40), and 1.4 (0.9-2.0, P = .09) for glutamine, antioxidant, and glutamine plus antioxidant arms, respectively. In the post hoc subgroup analysis, both glutamine and antioxidants appeared most harmful in patients with baseline renal dysfunction. No subgroups suggested reduced mortality with supplements. CONCLUSIONS: After adjustment for baseline covariates, early provision of high-dose glutamine administered separately from artificial nutrition was not beneficial and may be associated with increased mortality in critically ill patients with multiorgan failure. For both glutamine and antioxidants, the greatest potential for harm was observed in patients with multiorgan failure that included renal dysfunction upon study enrollment.

Implementation of bayesian therapeutic drug monitoring in modern patient care

The variability observed in drug exposure has a direct impact on the overall response to drug. The largest part of variability between dose and drug response resides in the pharmacokinetic phase, i.e. in the dose-concentration relationship. Among possibilities offered to clinicians, Therapeutic Drug Monitoring (TDM; Monitoring of drug concentration measurements) is one of the useful tool to guide pharmacotherapy. TDM aims at optimizing treatments by individualizing dosage regimens based on blood drug concentration measurement. Bayesian calculations, relying on population pharmacokinetic approach, currently represent the gold standard TDM strategy. However, it requires expertise and computational assistance, thus limiting its large implementation in routine patient care. The overall objective of this thesis was to implement robust tools to provide Bayesian TDM to clinician in modern routine patient care. To that endeavour, aims were (i) to elaborate an efficient and ergonomic computer tool for Bayesian TDM: EzeCHieL (ii) to provide algorithms for drug concentration Bayesian forecasting and software validation, relying on population pharmacokinetics (iii) to address some relevant issues encountered in clinical practice with a focus on neonates and drug adherence. First, the current stage of the existing software was reviewed and allows establishing specifications for the development of EzeCHieL. Then, in close collaboration with software engineers a fully integrated software, EzeCHieL, has been elaborated. EzeCHieL provides population-based predictions and Bayesian forecasting and an easy-to-use interface. It enables to assess the expectedness of an observed concentration in a patient compared to the whole population (via percentiles), to assess the suitability of the predicted concentration relative to the targeted concentration and to provide dosing adjustment. It allows thus a priori and a posteriori Bayesian drug dosing individualization. Implementation of Bayesian methods requires drug disposition characterisation and variability quantification trough population approach. Population pharmacokinetic analyses have been performed and Bayesian estimators have been provided for candidate drugs in population of interest: anti-infectious drugs administered to neonates (gentamicin and imipenem). Developed models were implemented in EzeCHieL and also served as validation tool in comparing EzeCHieL concentration predictions against predictions from the reference software (NONMEM®). Models used need to be adequate and reliable. For instance, extrapolation is not possible from adults or children to neonates. Therefore, this work proposes models for neonates based on the developmental pharmacokinetics concept. Patients' adherence is also an important concern for drug models development and for a successful outcome of the pharmacotherapy. A last study attempts to assess impact of routine patient adherence measurement on models definition and TDM interpretation. In conclusion, our results offer solutions to assist clinicians in interpreting blood drug concentrations and to improve the appropriateness of drug dosing in routine clinical practice.