A time-to-event model for acute rejections in paediatric renal transplant recipients treated with ciclosporin A.

AIMS: Ciclosporin A (CsA) dosing in immunosuppression after paediatric kidney transplantation remains challenging, and appropriate target CsA exposures (AUCs) are controversial. This study aimed to develop a time-to-first-acute rejection (AR) model and to explore predictive factors for therapy outcome. METHODS: Patient records at the Children's Hospital in Helsinki, Finland, were analysed. A parametric survival model in NONMEM was used to describe the time to first AR. The influences of AUC and other covariates were explored using stepwise covariate modelling, bootstrap-stepwise covariate modelling and cross-validated stepwise covariate modelling. The clinical relevance of the effects was assessed with the time at which 90% of the patients were AR free (t90). RESULTS: Data from 87 patients (0.7-19.8 years old, 54 experiencing an AR) were analysed. The baseline hazard was described with a function changing in steps over time. No statistically significant covariate effects were identified, a finding substantiated by all methods used. Thus, within the observed AUC range (90% interval 1.13-8.40 h mg l⁻¹), a rise in AUC was not found to increase protection from AR. Dialysis time, sex and baseline weight were potential covariates, but the predicted clinical relevance of their effects was low. For the strongest covariate, dialysis time, median t90 was 5.8 days (90% confidence interval 5.1-6.8) for long dialysis times (90th percentile) and 7.4 days (6.4-11.7) for short dialysis times (10th percentile). CONCLUSIONS: A survival model with discrete time-varying hazards described the data. Within the observed range, AUC was not identified as a covariate. This feedback on clinical practice may help to avoid unnecessarily high CsA dosing in children.

Beta-blockers for congestive heart failure in children.

BACKGROUND: Beta-blockers are an essential part of standard therapy in adult congestive heart failure and are therefore also expected to be beneficial in children. However, congestive heart failure in children differs strongly from that in adults in terms of characteristics and aetiology; also, an increased drug clearance has been reported. Paediatric needs have therefore to be specifically investigated. OBJECTIVES: To assess the effect of beta-adrenoceptor-blockers in children with congestive heart failure. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 4 2007), MEDLINE (1966 to January 2008), EMBASE (1980 to January 2008), and LILACS (1980 to January 2008). Bibliographies of identified studies were checked. No language restrictions were applied. SELECTION CRITERIA: Randomised, controlled clinical trials investigating the effect of beta-blocker therapy on paediatric congestive heart failure. DATA COLLECTION AND ANALYSIS: Two authors independently extracted and assessed data from the included trials. MAIN RESULTS: Three studies with an overall number of 203 participants were identified. Two small studies, with 20 and 22 children respectively, showed an improvement of congestive heart failure, while a larger study with 161 participants showed no evidence of benefit over placebo in the composite measure of heart failure outcomes which was the main outcome measure of the trial (56% improvement in both the placebo and the treatment group, p=0.74). However, study populations showed vast differences with regard to treatment (choice of beta-blocker, dosing, duration of treatment), age and age range of the participants and in particular with regard to condition (aetiology and severity of heart failure; homogeneity of condition in the study population). In addition methods and outcome measures differed strongly and were not standardised. The results can therefore not be compared against each other. AUTHORS' CONCLUSIONS: There are not enough data to recommend or discourage the use of beta-blockers in children with congestive heart failure. Further investigations in clearly defined populations with standardised methodology are required to establish guidelines for therapy. Pharmacokinetic investigations of beta-blockers in children are required to provide effective dosing in future trials.

Off-label drug use among hospitalised children: identifying areas with the highest need for research.

OBJECTIVE OF THE STUDY: To analyse the off-label use of drugs on a paediatric ward in Germany, and to identify domains of pharmacotherapy with the highest need for research concerning off-label use in children. SETTING: A prospective observational study was conducted on a paediatric ward in Duesseldorf in Germany between January and June 2006. METHOD: Data about patients, diagnoses and prescribed drugs were collected from the prescription records and the discharge letters. Diagnoses were classified in groups by means of the International Classification of Diseases. Drugs were grouped according to the Anatomical Therapeutic Chemical Classification system. We compared the off-label prescriptions with those on the list of paediatric needs and priority list established by the European Medicines Agency (EMEA). MAIN OUTCOME MEASURE: Off-label use was defined due to age, indication, route of application and dose. RESULTS: The study included 417 patients. We analysed 1,812 prescriptions representing 211 different drugs. In total, 253 patients (61%) received at least one off-label prescription. Of all analysed prescriptions, 553 (31%) were off-label. The percentage of off-label prescriptions among the five most frequently prescribed drug groups were as follows: 60% cardiovascular drugs (CV: 129/216), 42% anti-infectives (AI: 190/449), 30% drugs for respiratory system (RS: 100/335), 25% drugs for alimentary tract and metabolism (AM: 67/269) and 3% analgesics and antipyretics (AA: 8/264); with 17 drugs, the cardiovascular drugs also showed the highest number of different off-label prescribed drugs due to age: AI: 14; AM: 11; RS: 5; AA: 1. In addition, there was a nearly complete overlap between the identified off-label prescriptions in cardiovascular drugs and those listed by the EMEA to be prioritized for urgent research in Europe. CONCLUSION: Cardiovascular drugs are a domain of pharmacotherapy, with a large need for research in paediatrics. The results of our study can guide the researcher to future trials on off-label prescriptions such as cardiovascular drugs, especially due to the fact that the identified off-label prescribed drugs in this group are also mentioned by the EMEA to be prioritized for paediatric research.