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The BMJ and Cochrane call on government and health policy decision makers to review guidance on use of Tamiflu in light of most recent evidence
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Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
Background: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. Methods: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. Findings: Over 10 years, haemoglobin A(1c) (HbA(1c)) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group - an 11% reduction. There was no difference in HbA(1c) among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p = 0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p = 0.34) for any diabetes-related death; and 6% lower (-10 to 20, p = 0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p = 0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p < 0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p < 0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). Interpretation: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. None of the individual drugs had an adverse effect on cardiovascular outcomes. All intensive treatment increased the risk of hypoglycaemia.
Clinical and cost-effectiveness of a personalised guided consultation versus usual physiotherapy care in people presenting with shoulder pain: a protocol for the PANDA-S cluster randomised controlled trial and process evaluation
Introduction Musculoskeletal shoulder pain is a common reason for people to be treated in physiotherapy services, but diagnosis can be difficult and often does not guide treatment or predict outcome. People with shoulder pain cite a need for clear information, and timely, tailored consultations for their pain. This trial will evaluate the introduction of a personalised guided consultation to help physiotherapists manage care for individuals with shoulder pain. Methods and analysis This is a cluster randomised controlled trial to evaluate the clinical and cost-effectiveness of introducing a personalised guided consultation compared with usual UK NHS physiotherapy care. Physiotherapy services (n=16) will be randomised in a 1:1 ratio to either intervention (physiotherapy training package and personalised guided consultation incorporating a new prognostic tool) or control (usual care); 832 participants (416 in each arm) identified from participating physiotherapy service waiting lists aged 18 years or over with shoulder pain will be enrolled. Follow-up will occur at 3 time points: 6 weeks, 6 months and 12 months. The primary outcome will be the Shoulder Pain and Disability Index (SPADI) score over 12 months. Secondary outcomes include global perceived change of the shoulder condition, sleep, work absence and the impact of shoulder pain on work performance, healthcare utilisation and health-related quality of life (using EuroQol 5 Dimension 5 Level (EQ-5D-5L)). A multimethod process evaluation will investigate views and experiences of participants and physiotherapists, assess uptake, facilitators and barriers to delivery, and changes in factors assumed to explain intervention outcomes. Primary analysis of effectiveness will be by intention-to-treat, and a health economic evaluation will assess cost-utility of introducing the personalised consultation. Ethics and dissemination The trial received ethics approval from the Yorkshire & The Humber (South Yorkshire) Research Ethics Committee (REC reference: 23/YH/0070). Findings will be shared through journal publications, media outlets and conference presentations. Supported by patient contributors and clinical advisors, we will communicate findings through a designated website, networks, newsletters, leaflets and in the participating physiotherapy services.
Investigating the association between recorded smoking cessation interventions and smoking cessation in people living with cardiovascular disease using UK general practice data
Background: Smoking significantly increases the risk of cardiovascular diseases (CVD), yet quitting smoking after diagnosis of CVD can mitigate further negative impacts. However, encouraging smoking cessation remains a challenge for General Practitioners (GPs) with concerns regarding mental health. Since 2004, the UK’s Quality and Outcomes Framework (QOF) incentivises GP smoking cessation support. Despite this, a significant proportion of individuals diagnosed with CVD continue to smoke after diagnosis. This study aims to investigate the frequencies and types of smoking cessation interventions offered to people with CVD (defined as coronary heart disease (CHD) and stroke), with and without mental illness, and assess their association with successful cessation. Methods: This retrospective cohort study examined adults diagnosed with CHD or stroke using the QResearch general practice records database (1996–2019). We evaluated the frequency and types of smoking cessation interventions documented in patients’ records, including education, brief interventions, pharmacological support, referrals, and counselling. Logistic regression assessed the relationship between recorded interventions and smoking abstinence rates within the one-year post-index event, considering QOF incentives and mental illness presence. Results: While smoking cessation education was common in general practice settings, prescriptions for nicotine replacement therapy or other evidence-based interventions were comparatively low. CHD and stroke populations showed a significant association between any intervention and smoking cessation within one year (CHD: OR 1.41, 95% CI 1.36–1.45; stroke: OR 1.49, 95% CI 1.43–1.55). Education consistently correlated with higher cessation likelihoods, while other interventions were linked to lower rates. Individuals with common and serious mental illness were less likely to quit, irrespective of intervention. QOF implementation led to increased documentation of advice but not intensive support or treatment, with pre-QOF interventions associated with significantly increased abstinence likelihoods (CHD: OR 5.09, 95% CI 4.84–5.35; stroke: OR 4.44, 95% CI 4.07–4.86). Conclusions: Financial incentives for GP smoking cessation support outlined in QOF may not suffice to enhance methods that are more efficacious or improve cessation rates, especially among people with mental illness. Practical strategies that provide tangible support and treatment are needed for CVD patients, including those with mental illness, to facilitate successful cessation.
Impact of the COVID-19 pandemic on antidepressant prescribing with a focus on people with learning disability and autism: an interrupted time series analysis in England using OpenSAFELY-TPP.
BACKGROUND: COVID-19 restrictions led to increased reports of depressive symptoms in the general population and impacted health and social care services. We explored whether these changes affected antidepressant prescribing trends in the general population and those with learning disability or autism. METHODS: With the approval of NHS England, we used >24 million patients' primary care data from the OpenSAFELY-TPP platform. We used interrupted time series analysis to quantify trends in those prescribed and newly prescribed an antidepressant across key demographic and clinical subgroups, comparing pre-COVID-19 (January 2018-February 2020), COVID-19 restrictions (March 2020-February 2021) and recovery (March 2021-December 2022) periods. RESULTS: Prior to COVID-19 restrictions, antidepressant prescribing was increasing in the general population and in those with learning disability or autism. We did not find evidence that the pandemic was associated with a change in antidepressant prescribing trend in the general population (relative risk (RR) 1.00 (95% CI 0.97 to 1.02)), in those with autism (RR 0.99 (95% CI 0.97 to 1.01)) or in those with learning disability (RR 0.98 (95% CI 0.96 to 1.00)).New prescribing post restrictions was 13% and 12% below expected had COVID-19 not happened in both the general population and those with autism (RR 0.87 (95% CI 0.83 to 0.93), RR 0.88 (95% CI 0.83 to 0.92)), but not learning disability (RR 0.96 (95% CI 0.87 to 1.05)). CONCLUSIONS AND IMPLICATIONS: In this England study, we did not see an impact of COVID-19 on overall antidepressant prescribing, although unique trends were noted, such as trends in new antidepressant prescriptions which increased in care homes over the pandemic and decreased in the general population and those with autism since recovery.
Clinical Study Reports-a systematic review with thematic synthesis: Part 2. Studying benefits, harms, and the benefit to harm balance of pharmacological interventions.
BACKGROUND: We define clinical study reports (CSRs) as standardized full reports of the protocols, results, and other pertinent details of clinical studies that are typically submitted by pharmaceutical companies to regulatory authorities when they apply for marketing authorization. METHODS: In this systematic review we searched various databases (Clarivate Web of Science, EMBASE and Ovid Medline, Google Scholar, and PubMed) for publications containing the term "clinical study report/s", without restrictions. THEMATIC SYNTHESIS: In the first part of this review we discussed the history of CSRs, their contents and structure, definitions, and relevant terminology. In this second part we discuss the uses of CSRs, concentrating on the individual benefits and harms of pharmacological interventions, and thus the benefit to harm balance. We also discuss adherence to interventions, prepublication of protocols of clinical trials, and how CSRs are written, factors that can all affect estimation of the benefit-harm balance. CONCLUSIONS: When clinical trial data from CSRs are compared with the data in published trial reports, the apparent benefits of pharmacological interventions are less impressive, and more information emerges about harms they can cause. Both of these effects change how the benefit-harm balance of a pharmacological intervention is estimated, generally making it less favourable than was otherwise thought. For more accurate assessment of the benefit-harm balance of an intervention, full, not abbreviated or synoptic, clinical study reports should continue to be made publicly available by regulatory authorities and manufacturers. Authorities that do not currently make them available should do so. CSRs should be introduced for assessment of surgical operations, therapeutic devices, and other non-pharmacological interventions in clinical trials.
Clinical Study Reports-a systematic review with thematic synthesis: Part 1. History, contents and structure, definitions, and terminology.
BACKGROUND: Clinical study reports (CSRs) are standardized full reports of the protocols, results, and other pertinent details of clinical studies that are typically submitted by pharmaceutical companies to regulatory authorities, as part of the drug approval process. Their recommended contents and structure were described in 1995 in a document of the International Conference on Harmonisation, ICH E3, although companies can choose how to present the data. Until 2015, such reports were not readily available to the public, but since then some regulatory authorities have made them available, as have some pharmaceutical companies, albeit often in abbreviated or redacted versions. The apparent benefits of pharmacological interventions are not as impressive when they are calculated using data from clinical study reports compared with published trial reports, and more information emerges about harms the interventions can cause. RESULTS: Our methods are described in Part 2 of this systematic review with thematic synthesis, in which we have summarized the uses of CSRs, as described in 349 publications of various sorts, including analyses of clinical trials, data analyses, commentaries, and official documents. We have specifically concentrated on how CSRs affect assessments of benefits, harms, and the benefit-to-harm balance, and other factors that affect it. In Part 1, we discuss the history of the development of CSRs, their contents and structure, definitions of CSRs and qualifying terms, and relevant terminology (including the availability of CSRs, data sharing systems, and transparency and confidentiality). CONCLUSIONS: Our conclusions are listed in Part 2 of this review.
The implementation of a Nationally Enhanced Service incentive for weight management: A longitudinal qualitative study of the perceptions and experiences of UK primary care staff on weight management using normalisation process theory
SummaryIn 2021 a Nationally Enhanced Service (NES) incentive for weight management in primary care was rolled out in England. This paid general practices £11.50 for every eligible referral they made to a weight management programme. We explored primary care staff's perceptions, experiences and attitudes toward the NES by conducting 37 semi‐structured interviews with General Practitioners (GPs), administrative staff and nurses preceding the introduction of the NES (May to September 2021) and 1 year later following its introduction (September to December 2022). Data were analysed using normalisation process theory. The NES for weight management solidified the position of staff already supportive of referring patients to weight management programmes. For staff less supportive of weight management services, the dissonance between the perceived lack of benefit of services and making referrals to services was reduced with referrals becoming more habitual. Facilitators to implementation included the presence of a coherent national policy; having a ‘champion’ explain key aspects; and a financial incentive if framed as benefiting the practice at large. Barriers included a perception that primary care has been shouldered with a complex and difficult health crisis; a worry over workload burdens; and inefficient and unclear referral systems. The implementation of the NES was broadly welcomed and accepted by primary care staff. Interviewees expressed concerns around the acceptance of weight management policies in primary care, the provision of training to raise the topic of weight and whether the responsibility of weight management fell with primary care, public health or with the patient.
An overview of childhood cancer care and outcomes in Egypt: a narrative review
Childhood cancer is an urgent priority in Egypt, owing to a large number of children with cancer, the great need and demand for paediatric oncology services, limited resources/ funds and inferior survival outcomes. Therefore, an overview of the status of childhood cancer care in Egypt and an evidence-based approach towards optimal utilisation of resources/funds to improve this care are needed. This paper summarises key evidence about childhood cancer care and outcomes in Egypt. We conducted a narrative literature review using a structured search strategy of the MEDLINE database through the PubMed interface. All relevant evidence was summarised under five main sub-topics: (1) burden of childhood cancer in Egypt; (2) treatment approaches; (3) health outcomes; (4) costs and cost-effectiveness of treatment; and (5) barriers and facilitators to optimal childhood cancer care. We found high estimates of disease burden of childhood cancer in Egypt. Furthermore, childhood cancer treatment in Egypt is based on either implementing intensity-regulated protocols or adopting international protocols with or without adaptations to local contexts, leading to varying standards of care among the different treating centres. Limited data about the survival outcomes, costs and cost-effectiveness of treatment exist, although high-quality data from retrospective cohort studies were published from a large paediatric oncology centre (Children’s Cancer Hospital Egypt–57357). As Egypt joins the WHO Global Initiative for Childhood Cancers as a focus country, it is prepared to move towards streamlining national efforts to implement a national childhood cancer plan to advance care, improve health outcomes and optimise resource use. Through these efforts, Egypt could become a beacon of hope and a role model to other low- and middle-income countries seeking to improve their childhood cancer care.
Interventions for smokeless tobacco use cessation.
RATIONALE: While combustible tobacco has been the subject of a very large amount of research, smokeless tobacco products receive less attention. Most smokeless tobacco products are very harmful and cause global health inequality. It is therefore important to identify evidence-based cessation aids. OBJECTIVES: To assess the effects of behavioural and pharmacological interventions for smokeless tobacco use cessation. SEARCH METHODS: We searched the following databases from inception to 16 February 2024: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; PsycINFO; ClinicalTrials.gov (through CENTRAL); World Health Organisation International Clinical Trials Registry Platform (through CENTRAL). We also searched references of eligible studies. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) recruiting people of any age using smokeless tobacco, regardless of tobacco smoking status. Eligible studies could test any intervention designed to support people to quit smokeless tobacco use, and had to measure abstinence from either all tobacco use or smokeless tobacco use at six months or longer. OUTCOMES: The outcome of interest was abstinence from all tobacco use or from smokeless tobacco use at six months or longer. RISK OF BIAS: We used the Cochrane RoB 1 tool to assess bias in included studies. SYNTHESIS METHODS: We followed standard Cochrane methods for screening and data extraction. We grouped studies by comparisons of eligible interventions and comparators, reporting individual study and pooled effects as appropriate. We used a random-effects Mantel-Haenszel model for analyses of behavioural interventions and a fixed effect Mantel-Haenszel model for analyses of pharmacotherapies to calculate risk ratios (RR) with 95% confidence intervals (CI). We assessed the certainty of evidence using GRADE. INCLUDED STUDIES: We included 43 trials of 20,346 people. Thirty-three trials were conducted in North America, five in India, two in Scandinavia, one in Pakistan and one in Turkey. One study was conducted across multiple sites in Bangladesh, India and Pakistan. Studies tested behavioural interventions (e.g. cessation counselling and brief advice) and pharmacotherapies (e.g. nicotine replacement therapy (NRT), varenicline, and bupropion). We judged five studies to be at low risk of bias overall, 22 at high risk of bias, and the remaining 16 at unclear risk of bias. SYNTHESIS OF RESULTS: We found moderate-certainty evidence of increased quit rates from counselling compared with minimal support (RR 1.76, 95% CI 1.44 to 2.16; I2 = 69%; 21 studies, n = 7417; downgraded because of heterogeneity), brief advice compared with no support (RR 1.24, 95% CI 1.03 to 1.48; I2 = 49%; 7 studies, n = 6271; downgraded because of imprecision), and varenicline compared with placebo (RR 1.35, 95% CI 1.08 to 1.68; I2 = 0%; 2 studies, n = 508; downgraded because of imprecision). We found low-certainty evidence (downgraded because of imprecision and risk of bias) of increased quit rates from NRT compared with placebo or no medication (RR 1.18, 95% CI 1.05 to 1.33; I2 = 39%; 11 studies, n = 2826). Low-certainty evidence (downgraded because of imprecision) did not show benefit from bupropion compared with placebo (RR 0.89, 95% CI 0.54 to 1.44; I2 = 0%; 2 studies, n = 293). We planned subgroup analyses to explore whether smokeless tobacco type affects intervention efficacy, but found insufficient data. AUTHORS' CONCLUSIONS: Cessation counselling, brief advice, and varenicline each probably help more people to quit smokeless tobacco use than minimal or no support, or placebo. NRT may help more people to quit smokeless tobacco use than placebo or no medication. Low-certainty evidence does not currently support bupropion as a smokeless tobacco cessation intervention. Despite the majority of smokeless tobacco users living in South and Southeast Asia, only a minority of trials are conducted in those regions. Future trials should address this imbalance. FUNDING: None REGISTRATION: Protocol available via DOI: 10.1002/14651858.CD015314.
Defining success in adult obesity management: A systematic review and framework synthesis of clinical practice guidelines
Obesity is a chronic and complex disease affecting millions of people worldwide. Currently, there is no standard definition of success for the management of obesity. We set out to complete a synthesis of clinical practice guidelines for obesity management for adult populations, aiming to provide both a quantitative descriptive and qualitative analysis of definitions of success in clinical practice guidelines. An electronic search retrieved 4477 references. Sixteen clinical practice guidelines were included after screening and full-text review. We coded definitions of success 147 times across the included guidelines. No standard or explicit definition of success was identified in the guidelines but rather success was implicitly defined. We developed three themes describing how success was defined in the clinical practice guidelines: Knowledge-based decision making; management of expectations; and the perception of control. The review reinforced that success is an inherently subjective and complex concept. Defining success is limited by existing studies that focus on weight loss and would benefit from additional research on different outcomes. Equally, the relationship between people living with obesity and their clinicians should be further explored to understand how defining success is controlled, discussed and framed in a clinical setting.