Ruwanthi Kolamunnage-Dona

Patients with epilepsy: Cognitively compromised before the start of antiepileptic drug treatment?

Purpose:  To compare the cognitive profile of newly diagnosed untreated epilepsy patients with healthy volunteers using a comprehensive neuropsychological test battery.

Enhanced relapse prevention for bipolar disorder by community mental health teams: cluster feasibility randomised trial

BACKGROUND Relapse prevention for bipolar disorder increases time to relapse but is not available in routine practice. AIMS To determine the feasibility and effectiveness of training community mental health teams (CMHTs) to deliver enhanced relapse prevention. METHOD In a cluster randomised controlled trial, CMHT workers were allocated to receive 12 h training in enhanced relapse prevention to offer to people with bipolar disorder or to continue giving treatment as usual. The primary outcome was time to relapse and the secondary outcome was functioning. RESULTS Twenty-three CMHTs and 96 service users took part. Compared with treatment as usual, enhanced relapse prevention increased median time to the next bipolar episode by 8.5 weeks (hazard ratio 0.79, 95% CI 0.45-1.38). Social and occupational functioning improved with the intervention (regression coefficient 0.68, 95% CI 0.05-1.32). The clustering effect was negligible but imprecise (intracluster correlation coefficient 0.0001, 95% CI 0.0000-0.5142). CONCLUSIONS Training care coordinators to offer enhanced relapse prevention for bipolar disorder may be a feasible effective treatment. Large-scale cluster trials are needed.

Assessing the potential for outcome reporting bias in a review: a tutorial

BackgroundOutcome reporting bias (ORB) occurs when variables are selected for publication based on their results. This can impact upon the results of a meta-analysis, biasing the pooled treatment effect estimate.The aim of this paper is to show how to assess a systematic review and corresponding trial reports for ORB using an example review of intravenous and nebulised magnesium in the treatment of asthma.MethodsThe review was assessed for ORB by 1) checking the reasons, when available, for excluding studies to ensure that no studies were excluded because they did not report the outcomes of interest in the review; 2) assessing the eligible studies as to whether the review outcomes of interest were reported. Each study was classified using a system developed in the ORBIT (Outcome Reporting Bias In Trials) project to indicate whether ORB was suspected and a reason for the suspicion. Authors of trials that did not report the outcomes of interest were contacted for information. A sensitivity analysis was performed to assess the robustness of the conclusions of the review to this potential source of bias.ResultsTwenty-four studies were included in the review; two studies had been excluded for not reporting either of the two outcomes of interest. Six included studies did not report hospital admission and two did not report pulmonary function. There was high suspicion of outcome reporting bias in four studies. Results from the sensitivity analysis indicate that review conclusions were not overturned.ConclusionThis paper demonstrates, with the example of the magnesium review, how to assess a review for outcome reporting bias. A review should not exclude studies if they have not reported the outcomes of interest and should consider the potential for outcome reporting bias in all included studies.

Joint modelling of longitudinal and competing risks data.

Available methods for joint modelling of longitudinal and survival data typically have only one failure type for the time to event outcome. We extend the methodology to allow for competing risks data. We fit a cause-specific hazards sub-model to allow for competing risks, with a separate latent association between longitudinal measurements and each cause of failure.The method is applied to data from the SANAD trial of anti-epileptic drugs (AEDs), as a means of investigating the effect of drug titration on the relative effects of lamotrigine (LTG) and carbamazepine (CBZ) on treatment failure. Concern had been expressed that differential titration rates may have been to the disadvantage of CBZ. The beneficial effect of LTG on unacceptable adverse events leading to drug withdrawal did not lessen and indeed increased slightly when a calibrated dose was accounted for in the joint model. Adjustment for the titration rate of LTG relative to CBZ resulted in an unchanged effect of the former on drug withdrawals due to inadequate seizure control. LTG remains the AED of choice from this analysis.

Magnesium sulphate in acute severe asthma in children (MAGNETIC): a randomised, placebo-controlled trial

BACKGROUND Little evidence is available for the effect of nebulised magnesium sulphate (MgSO(4)) in acute asthma in children. We assessed the effect of MgSO(4) treatment in children with severe acute asthma. METHODS In this randomised placebo-controlled, multi-centre, parallel trial, we enrolled children (aged 2-16 years) with severe acute asthma who did not respond to standard inhaled treatment from 30 hospitals in the UK. Children were randomly allocated (1:1) to receive nebulised salbutamol and ipratropium bromide with either 2·5 mL of isotonic MgSO(4) (250 mmol/L; 151 mg per dose; MgSO(4) group) or 2·5 mL of isotonic saline (placebo group) on three occasions at 20-min intervals. Randomisation was done with a computer-generated randomisation sequence, with random block sizes of two to four. Both patients and researchers were masked to treatment allocation. The primary outcome measure was the Yung Asthma Severity Score (ASS) at 60 min post-randomisation. We used a statistical significance level of p<0·05 for a between-group difference, but regarded a between-group difference in ASS of 0·5 as the minimal clinically significant treatment effect. Analysis was done by intention to treat. This trial is registered with controlled-trials.com, number ISRCTN81456894. FINDINGS Between Jan 3, 2009, and March 20, 2011, we recruited and randomly assigned 508 children to treatment: 252 to MgSO(4) and 256 to placebo. Mean ASS at 60 min was lower in the MgSO(4) group (4·72 [SD 1·37]) than it was in the placebo group (4·95 [SD 1·40]; adjusted difference -0·25, 95% CI -0·48 to -0·02; p=0·03). This difference, however, was not clinically significant. The clinical effect was larger in children with more severe asthma exacerbation (p=0·03) and those with symptoms present for less than 6 h (p=0·049). We detected no difference in the occurrence of adverse events between groups. INTERPRETATION Overall, nebulised isotonic MgSO(4), given as an adjuvant to standard treatment, did not show a clinically significant improvement in mean ASS in children with acute severe asthma. However, the greatest clinical response was seen in children with more severe attacks (SaO(2)<92%) at presentation and those with preceding symptoms lasting less than 6 h. FUNDING National Institute for Health Research Health Technology Assessment Programme.

Biomarker-Guided Adaptive Trial Designs in Phase II and Phase III: A Methodological Review

Background Personalized medicine is a growing area of research which aims to tailor the treatment given to a patient according to one or more personal characteristics. These characteristics can be demographic such as age or gender, or biological such as a genetic or other biomarker. Prior to utilizing a patient’s biomarker information in clinical practice, robust testing in terms of analytical validity, clinical validity and clinical utility is necessary. A number of clinical trial designs have been proposed for testing a biomarker’s clinical utility, including Phase II and Phase III clinical trials which aim to test the effectiveness of a biomarker-guided approach to treatment; these designs can be broadly classified into adaptive and non-adaptive. While adaptive designs allow planned modifications based on accumulating information during a trial, non-adaptive designs are typically simpler but less flexible. Methods and Findings We have undertaken a comprehensive review of biomarker-guided adaptive trial designs proposed in the past decade. We have identified eight distinct biomarker-guided adaptive designs and nine variations from 107 studies. Substantial variability has been observed in terms of how trial designs are described and particularly in the terminology used by different authors. We have graphically displayed the current biomarker-guided adaptive trial designs and summarised the characteristics of each design. Conclusions Our in-depth overview provides future researchers with clarity in definition, methodology and terminology for biomarker-guided adaptive trial designs.

Depressive and manic symptoms are not opposite poles in bipolar disorder.

Johnson SL, Morriss R, Scott J, Paykel E, Kinderman P, Kolamunnage‐Dona R, Bentall RP. Depressive and manic symptoms are not opposite poles in bipolar disorder.

Prasugrel for the treatment of acute coronary artery syndromes with percutaneous coronary intervention.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of prasugrel for the treatment of coronary artery syndromes with percutaneous coronary intervention, based upon the evidence submission from Eli Lilly to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence was based on a phase III double-blind, double-dummy randomised controlled trial which compared the use of prasugrel with clopidogrel. The primary clinical outcome measure was a composite end point of death from cardiovascular causes, non-fatal myocardial infarction (MI) or non-fatal stroke at 15 months. Secondary outcomes included the primary end point at 30 days and 90 days; a composite end point of death from cardiovascular causes, non-fatal MI or urgent target vessel revascularisation; a composite end point of death from cardiovascular causes, non-fatal MI, non-fatal stroke or rehospitalisation due to a cardiac ischaemic event; and stent thrombosis. For the overall trial cohort during the 15 month follow-up period, the results of the trial demonstrated a statistically significant benefit of prasugrel compared with clopidogrel on the primary outcome. The efficacy difference between treatment groups was, in the main, due to a statistically significant lower incidence of non-fatal MIs in the prasugrel group than in the clopidogrel group. No statistically significant differences were found for death from cardiovascular causes or non-fatal stroke. For the fully licensed and target populations, there was a statistically significant lower incidence of non-fatal MIs in the prasugrel group than in the clopidogrel group; there was no statistically significant difference in bleeding rates. The ERG recalculated the base-case cost-effectiveness results taking changes in parameters and assumptions into account: for example, revised drug costs, mid-cycle correction, amended relative risk mortality. Subgroup and threshold analyses were also explored by the ERG. For the fully licensed population (i.e. excluding patients with prior stroke or TIA), the manufacturer reported an incremental cost-effectiveness ratio (ICER) of 159,358 pounds per quality-adjusted life-year (QALY) gained at 12 months and an ICER of 3,220 pounds per QALY gained at 40 years. Considering the 15-month clinical trial data available for the fully licensed and target populations and current practice in England and Wales, the evidence was considered insufficient to support the conclusion that prasugrel is clinically more effective than clopidogrel or vice versa. Assuming that there is no evidence to distinguish between prasugrel and clopidogrel in terms of clinical effectiveness in the short term for this population, equipoise between prasugrel and clopidogrel at year 1 is achieved by a 20% reduction in the acquisition cost of prasugrel (approximately 120 pounds per patient). At the time of writing, the guidance/has not yet been published by NICE.

Assessment and clinical course of hypocalcemia in critical illness

IntroductionHypocalcemia is common in critically ill patients. However, its clinical course during the early days of admission and the role of calcium supplementation remain uncertain, and the assessment of calcium status is inconsistent. We aimed to establish the course of hypocalcemia during the early days of critical illness in relation to mortality and to assess the impact of calcium supplementation on calcium normalization and mortality.MethodsData were collected on 1,038 admissions to the critical care units of a tertiary care hospital. One gram of calcium gluconate was administered intravenously once daily to patients with adjusted calcium (AdjCa) <2.2 mmol/L. Demographic and outcome data were compared in normocalcemic (ionized calcium, iCa, 1.1-1.3 mmol/L) and mildly and severely hypocalcemic patients (iCa 0.9-1.1 mmol/L and <0.9 mmol/L, respectively). The change in iCa concentrations was monitored during the first four days of admission and comparisons between groups were made using Repeated Measures ANOVA. Comparisons of normalization and outcome were made between hypocalcemic patients who did and did not receive calcium replacement according to the local protocol. The suitability of AdjCa to predict low iCa was determined by analyzing sensitivity, specificity and receiver operating characteristic (ROC) curves. Multivariate logistic regression was performed to determine associations of other electrolyte derangements with hypocalcemia.Results55.2% of patients were hypocalcemic on admission; 6.2% severely so. Severely hypocalcemic patients required critical care for longer (P = 0.001) compared to normocalcemic or mildly hypocalcemic patients, but there was no difference in mortality between groups (P = 0.48). iCa levels normalized within four days in most, with no difference in normalization between those who died and survived (P = 0.35). Severely hypocalcemic patients who failed to normalize their iCa by day 4 had double the mortality (38% vs. 19%, P = 0.15). Neither iCa normalization nor survival were superior in hypocalcemic patients receiving supplementation on admission. AdjCa <2.2 mmol/L had a sensitivity of 78.2% and specificity of 63.3% for predicting iCa <1.1 mmol/L. Low magnesium, sodium and albumin were independently associated with hypocalcemia on admission.ConclusionsHypocalcemia usually normalizes within the first four days after admission to ICU and failure to normalize in severely hypocalcemic patients may be associated with increased mortality. Calcium replacement appears not to improve normalization or mortality. AdjCa is not a good surrogate of iCa in an ICU setting.

Joint modelling of time-to-event and multivariate longitudinal outcomes: recent developments and issues

BackgroundAvailable methods for the joint modelling of longitudinal and time-to-event outcomes have typically only allowed for a single longitudinal outcome and a solitary event time. In practice, clinical studies are likely to record multiple longitudinal outcomes. Incorporating all sources of data will improve the predictive capability of any model and lead to more informative inferences for the purpose of medical decision-making.MethodsWe reviewed current methodologies of joint modelling for time-to-event data and multivariate longitudinal data including the distributional and modelling assumptions, the association structures, estimation approaches, software tools for implementation and clinical applications of the methodologies.ResultsWe found that a large number of different models have recently been proposed. Most considered jointly modelling linear mixed models with proportional hazard models, with correlation between multiple longitudinal outcomes accounted for through multivariate normally distributed random effects. So-called current value and random effects parameterisations are commonly used to link the models. Despite developments, software is still lacking, which has translated into limited uptake by medical researchers.ConclusionAlthough, in an era of personalized medicine, the value of multivariate joint modelling has been established, researchers are currently limited in their ability to fit these models routinely. We make a series of recommendations for future research needs.