Web-based self-management support for people with type 2 diabetes (HeLP-Diabetes): randomised controlled trial in English primary care

OBJECTIVE: To determine the effectiveness of a web-based self-management programme for people with type 2 diabetes in improving glycaemic control and reducing diabetes-related distress. METHODS: Design: Individually randomised two-arm controlled trial Setting: 21 General Practices in England Participants: Adults aged 18 or over with a diagnosis of type 2 diabetes registered with participating general practices Intervention and comparator: Usual care plus either HeLP-Diabetes, an interactive, theoretically informed, web-based self-management programme or a simple, text-based website containing basic information only. Outcomes and data collection: Joint primary outcomes were glycated haemoglobin (HbA1c) and diabetes-related distress, measured by the Problem Areas in Diabetes (PAID) scale, collected at 3 and 12 months after randomisation, with 12 months the primary outcome point. Research nurses, blind to allocation collected clinical data; participants completed self-report questionnaires online. Analysis: The analysis compared groups as randomised (intention to treat) using a linear mixed effects model, adjusted for baseline data with multiple imputation of missing values. RESULTS: Of the 374 participants randomised between September 2013 and December 2014, 185 were allocated to the intervention and 189 to the control. Final (12 month) follow up data for HbA1c were available for 318 (85%) and for PAID 337 (90%) of participants. Of these, 291 (78%) and 321 (86%) responses were recorded within the pre-defined “window” of 10-14 months. Participants in the intervention group had lower HbA1c than those in the control (mean difference -0.24%; 95% Confidence Interval -0.44 to -0.049; p=0.014). There was no significant overall difference between groups in the mean PAID score (p=0.21), but pre-specified subgroup analysis of participants who had had diabetes for less than 7 years showed a beneficial impact of the intervention in this group (p = 0.004). There were no reported harms. CONCLUSIONS: Access to HeLP-Diabetes improved glycaemic control over 12 months.This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-0609-10135). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The funder had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Work conducted at the Cardiovascular Epidemiology Unit, University of Cambridge by MS and MH was additionally funded by the UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194) and UK National Institute for Health Research Cambridge Biomedical Research Centre. AF is an NIHR Senior Investigator and receives funding from Oxford NIHR Biomedical Research Centre

Systematic review and meta-analysis of the growth and rupture rates of small abdominal aortic aneurysms: implications for surveillance intervals and their cost-effectiveness.

BACKGROUND: Small abdominal aortic aneurysms (AAAs; 3.0-5.4 cm in diameter) are usually asymptomatic and managed by regular ultrasound surveillance until they grow to a diameter threshold (commonly 5.5 cm) at which surgical intervention is considered. The choice of appropriate surveillance intervals is governed by the growth and rupture rates of small AAAs, as well as their relative cost-effectiveness. OBJECTIVES: The aim of this series of studies was to inform the evidence base for small AAA surveillance strategies. This was achieved by literature review, collation and analysis of individual patient data, a focus group and health economic modelling. DATA SOURCES: We undertook systematic literature reviews of growth rates and rupture rates of small AAAs. The databases MEDLINE, EMBASE on OvidSP, Cochrane Central Register of Controlled Trials 2009 Issue 4, ClinicalTrials.gov, and controlled-trials.com were searched from inception up until the end of 2009. We also obtained individual data on 15,475 patients from 18 surveillance studies. REVIEW METHODS: Systematic reviews of publications identified 15 studies providing small AAA growth rates, and 14 studies with small AAA rupture rates, up to December 2009 (later updated to September 2012). We developed statistical methods to analyse individual surveillance data, including the effects of patient characteristics, to inform the choice of surveillance intervals and provide inputs for health economic modelling. We updated an existing health economic model of AAA screening to address the cost-effectiveness of different surveillance intervals. RESULTS: In the literature reviews, the mean growth rate was 2.3 mm/year and the reported rupture rates varied between 0 and 1.6 ruptures per 100 person-years. Growth rates increased markedly with aneurysm diameter, but insufficient detail was available to guide surveillance intervals. Based on individual surveillance data, for each 0.5-cm increase in AAA diameter, growth rates increased by about 0.5 mm/year and rupture rates doubled. To control the risk of exceeding 5.5 cm to below 10% in men, on average a 7-year surveillance interval is sufficient for a 3.0-cm aneurysm, whereas an 8-month interval is necessary for a 5.0-cm aneurysm. To control the risk of rupture to below 1%, the corresponding estimated surveillance intervals are 9 years and 17 months. Average growth rates were higher in smokers (by 0.35 mm/year) and lower in patients with diabetes (by 0.51 mm/year). Rupture rates were almost fourfold higher in women than men, doubled in current smokers and increased with higher blood pressure. Increasing the surveillance interval from 1 to 2 years for the smallest aneurysms (3.0-4.4 cm) decreased costs and led to a positive net benefit. For the larger aneurysms (4.5-5.4 cm), increasing surveillance intervals from 3 to 6 months led to equivalent cost-effectiveness. LIMITATIONS: There were no clear reasons why the growth rates varied substantially between studies. Uniform diagnostic criteria for rupture were not available. The long-term cost-effectiveness results may be susceptible to the modelling assumptions made. CONCLUSIONS: Surveillance intervals of several years are clinically acceptable for men with AAAs in the range 3.0-4.0 cm. Intervals of around 1 year are suitable for 4.0-4.9-cm AAAs, whereas intervals of 6 months would be acceptable for 5.0-5.4-cm AAAs. These intervals are longer than those currently employed in the UK AAA screening programmes. Lengthening surveillance intervals for the smallest aneurysms was also shown to be cost-effective. Future work should focus on optimising surveillance intervals for women, studying whether or not the threshold for surgery should depend on patient characteristics, evaluating the usefulness of surveillance for those with aortic diameters of 2.5-2.9 cm, and developing interventions that may reduce the growth or rupture rates of small AAAs. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Discrete Event Simulation for Decision Modeling in Health Care: Lessons from Abdominal Aortic Aneurysm Screening

Markov models are often used to evaluate the cost-effectiveness of new healthcare interventions but they are sometimes not flexible enough to allow accurate modeling or investigation of alternative scenarios and policies. A Markov model previously demonstrated that a one-off invitation to screening for abdominal aortic aneurysm (AAA) for men aged 65 y in the UK and subsequent follow-up of identified AAAs was likely to be highly cost-effective at thresholds commonly adopted in the UK (£20,000 to £30,000 per quality adjusted life-year). However, new evidence has emerged and the decision problem has evolved to include exploration of the circumstances under which AAA screening may be cost-effective, which the Markov model is not easily able to address. A new model to handle this more complex decision problem was needed, and the case of AAA screening thus provides an illustration of the relative merits of Markov models and discrete event simulation (DES) models. An individual-level DES model was built using the R programming language to reflect possible events and pathways of individuals invited to screening v. those not invited. The model was validated against key events and cost-effectiveness, as observed in a large, randomized trial. Different screening protocol scenarios were investigated to demonstrate the flexibility of the DES. The case of AAA screening highlights the benefits of DES, particularly in the context of screening studies

Making predictions from complex longitudinal data, with application to planning monitoring intervals in a national screening programme.

When biological or physiological variables change over time, we are often interested in making predictions either of future measurements or of the time taken to reach some threshold value. On the basis of longitudinal data for multiple individuals, we develop Bayesian hierarchical models for making these predictions together with their associated uncertainty. Particular aspects addressed, which include some novel components, are handling curvature in individuals' trends over time, making predictions for both underlying and measured levels, making predictions from a single baseline measurement, making predictions from a series of measurements, allowing flexibility in the error and random-effects distributions, and including covariates. In the context of data on the expansion of abdominal aortic aneurysms over time, where reaching a certain threshold leads to referral for surgery, we discuss the practical application of these models to the planning of monitoring intervals in a national screening programme. Prediction of the time to reach a threshold was too imprecise to be practically useful, and we focus instead on limiting the probability of exceeding the threshold after given time intervals. Although more complex models can be shown to fit the data better, we find that relatively simple models seem to be adequate for planning monitoring intervals

Toxicity-dependent feasibility bounds for the escalation with overdose control approach in phase I cancer trials

Phase I trials of anti-cancer therapies aim to identify a maximum tolerated dose (MTD), defined as the dose that causes unacceptable toxicity in a target proportion of patients. Both rule-based and model-based methods have been proposed for MTD recommendation. The escalation with overdose control (EWOC) approach is a model-based design where the dose assigned to the next patient is one that, given all available data, has a posterior probability of exceeding the MTD equal to a pre-specified value known as the feasibility bound. The aim is to conservatively dose-escalate and approach the MTD, avoiding severe overdosing early on in a trial. The EWOC approach has been applied in practice with the feasibility bound either fixed or varying throughout a trial, yet some of the methods may recommend incoherent dose-escalation, that is, an increase in dose after observing severe toxicity at the current dose. We present examples where varying feasibility bounds have been used in practice, and propose a toxicity-dependent feasibility bound approach that guarantees coherent dose-escalation and incorporates the desirable features of other EWOC approaches. We show via detailed simulation studies that the toxicity-dependent feasibility bound approach provides improved MTD recommendation properties to the original EWOC approach for both discrete and continuous doses across most dose-toxicity scenarios, with comparable performance to other approaches without recommending incoherent dose escalation.G. M. Wheeler and A. P. Mander are supported by the UK Medical Research Council (grant number G0800860). M. J. Sweeting is supported by a European Research Council Advanced Investigator Award: EPIC-Heart (grant number 268834), the UK Medical Research Council (grant number MR/L003120/1), the British Heart Foundation and the Cambridge National Institute for Health Research Biomedical Research Centre

AplusB: A Web Application for Investigating A plus B Designs for Phase I Cancer Clinical Trials

In phase I cancer clinical trials, the maximum tolerated dose of a new drug is often found by a dose-escalation method known as the A + B design. We have developed an interactive web application, AplusB, which computes and returns exact operating characteristics of A + B trial designs. The application has a graphical user interface (GUI), requires no programming knowledge and is free to access and use on any device that can open an internet browser. A customised report is available for download for each design that contains tabulated operating characteristics and informative plots, which can then be compared with other dose-escalation methods. We present a step-by-step guide on how to use this application and provide several illustrative examples of its capabilities

Comparative clinical effectiveness and cost effectiveness of endovascular strategy vs open repair for ruptured abdominal aortic aneurysm: three year results of the IMPROVE randomised trial

Objective To assess the three year clinical outcomes and cost effectiveness of a strategy of endovascular repair (if aortic morphology is suitable, open repair if not) versus open repair for patients with suspected ruptured abdominal aortic aneurysm. Design Randomised controlled trial. Participants 613 eligible patients (480 men) with a clinical diagnosis of ruptured aneurysm, of whom 502 underwent emergency repair for rupture. Interventions 316 patients were randomised to an endovascular strategy (275 with confirmed rupture) and 297 to open repair (261 with confirmed rupture). Main outcome measures Mortality, with reinterventions after aneurysm repair, quality of life, and hospital costs to three years as secondary measures. Results The maximum follow-up for mortality was 7.1 years, with two patients in each group lost to follow-up by three years. After similar mortality by 90 days, in the mid-term (three months to three years) there were fewer deaths in the endovascular than the open repair group (hazard ratio 0.57, 95% confidence interval 0.36 to 0.90), but by seven years mortality was about 60% in each group (hazard ratio 0.92, 0.75 to 1.13). Results for the 502 patients with repaired ruptures were more pronounced: three year mortality was lower in the endovascular strategy group (42% v 54%; odds ratio 0.62, 0.43 to 0.88), but after seven years there was no clear difference between the groups (hazard ratio 0.86, 0.68 to 1.08). Reintervention rates up to three years were not significantly different between the randomised groups (hazard ratio 1.02, 0.79 to 1.32); the initial rapid rate of reinterventions was followed by a much slower mid-term reintervention rate in both groups. The early higher average quality of life in the endovascular strategy versus open repair group, coupled with the lower mortality at three years, led to a gain in average quality adjusted life years (QALYs) at three years of 0.17 (95% confidence interval 0.00 to 0.33). The endovascular strategy group spent fewer days in hospital and had lower average costs of −£2605 (€2813; $3439) (95% confidence interval −£5966 to £702). The probability that the endovascular strategy is cost effective was >90% at all levels of willingness to pay for a QALY gain. Conclusions At three years, compared with open repair, an endovascular strategy for suspected ruptured abdominal aortic aneurysm was associated with a survival advantage, a gain in QALYs, similar levels of reintervention, and reduced costs, and this strategy was cost effective. These findings support the increasing use of an endovascular strategy, with wider availability of emergency endovascular repair. Trial registration Current Controlled Trials ISRCTN48334791; ClinicalTrials NCT00746122This project was funded by the UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project No 07/37/64). The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, National Health Service, or the Department of Health. Neither the funder nor the sponsor had any role in study design, data collection, analysis and interpretation of the findings

Lessons learned about prevalence and growth rates of abdominal aortic aneurysms from a 25-year ultrasound population screening programme

Background This study aims to assess how the prevalence and growth rates of small and medium AAAs (3.0-5.4cm) have changed over time in men aged 65 years, and to evaluate long-term outcomes in those men whose aortic diameter is 2.6-2.9cm (subaneurysmal), and below the standard threshold for most surveillance programmes. Methods The Gloucestershire Aneurysm Screening Programme (GASP) started in 1990. Men aged 65 years with an aortic diameter of 2.6-5.4cm, as measured by ultrasound using the inner to inner wall method, were included in surveillance. Aortic diameter growth rates were estimated separately for men who initially had a subaneurysmal aorta, or who had a small or medium AAA, using mixed-effects models. Results Since 1990, 81,150 men had ultrasound screening for AAA (uptake 80.7%), of whom 2,795 had an aortic diameter of 2.6-5.4cm. The prevalence of screen-detected AAA ≥3.0cm decreased from 5.0% in 1991 to 1.3% in 2015. There was no evidence of a change in AAA growth rates during this time. Of men who initially had a subaneurysmal aorta, 58% (95% CI 54, 61) were estimated to develop an AAA ≥3.0cm within 5 years of their initial scan, and 28% (95% CI 24, 32) were estimated to develop a large AAA (≥5.5cm) within 15 years. Conclusions The prevalence of screen-detected small and medium AAA has decreased over the last 25 years, but growth rates have remained similar. Men with a subaneurysmal aorta at age 65 have a substantial risk of developing a large AAA by the age of 80 years.Before its adoption into the national programme, GASP was funded by Gloucestershire Hospitals NHS Foundation Trust. The present research was facilitated by a grant from the Gloucester Vascular Research Trust Fund

Misspecification of at-risk periods and distributional assumptions in estimating COPD exacerbation rates: The resultant bias in treatment effect estimation.

In trials comparing the rate of chronic obstructive pulmonary disease exacerbation between treatment arms, the rate is typically calculated on the basis of the whole of each patient's follow-up period. However, the true time a patient is at risk should exclude periods in which an exacerbation episode is occurring, because a patient cannot be at risk of another exacerbation episode until recovered. We used data from two chronic obstructive pulmonary disease randomized controlled trials and compared treatment effect estimates and confidence intervals when using two different definitions of the at-risk period. Using a simulation study we examined the bias in the estimated treatment effect and the coverage of the confidence interval, using these two definitions of the at-risk period. We investigated how the sample size required for a given power changes on the basis of the definition of at-risk period used. Our results showed that treatment efficacy is underestimated when the at-risk period does not take account of exacerbation duration, and the power to detect a statistically significant result is slightly diminished. Correspondingly, using the correct at-risk period, some modest savings in required sample size can be achieved. Using the proposed at-risk period that excludes recovery times requires formal definitions of the beginning and end of an exacerbation episode, and we recommend these be always predefined in a trial protocol.Martin Law is used by the UK Medical Research Council (Funding, NIHR grant RP-PG-0109-10056)