Emmert Roberts

Paracetamol: not as safe as we thought? A systematic literature review of observational studies

Objectives We conducted a systematic literature review to assess the adverse event (AE) profile of paracetamol. Methods We searched Medline and Embase from database inception to 1 May 2013. We screened for observational studies in English, which reported mortality, cardiovascular, gastrointestinal (GI) or renal AEs in the general adult population at standard analgesic doses of paracetamol. Study quality was assessed using Grading of Recommendations Assessment, Development and Evaluation. Pooled or adjusted summary statistics were presented for each outcome. Results Of 1888 studies retrieved, 8 met inclusion criteria, and all were cohort studies. Comparing paracetamol use versus no use, of two studies reporting mortality one showed a dose–response and reported an increased relative rate of mortality from 0.95 (0.92 to 0.98) to 1.63 (1.58 to 1.68). Of four studies reporting cardiovascular AEs, all showed a dose–response with one reporting an increased risk ratio of all cardiovascular AEs from 1.19 (0.81 to 1.75) to 1.68 (1.10 to 2.57). One study reporting GI AEs reported a dose–response with increased relative rate of GI AEs or bleeds from 1.11 (1.04 to 1.18) to 1.49 (1.34 to 1.66). Of four studies reporting renal AEs, three reported a dose–response with one reporting an increasing OR of ≥30% decrease in estimated glomerular filtration rate from 1.40 (0.79 to 2.48) to 2.19 (1.4 to 3.43). Discussion Given the observational nature of the data, channelling bias may have had an important impact. However, the dose–response seen for most endpoints suggests a considerable degree of paracetamol toxicity especially at the upper end of standard analgesic doses.

The diagnostic accuracy of the natriuretic peptides in heart failure: systematic review and diagnostic meta-analysis in the acute care setting

Objectives To determine and compare the diagnostic accuracy of serum natriuretic peptide levels (B type natriuretic peptide, N terminal probrain natriuretic peptide (NTproBNP), and mid-regional proatrial natriuretic peptide (MRproANP)) in people presenting with acute heart failure to acute care settings using thresholds recommended in the 2012 European Society of Cardiology guidelines for heart failure. Design Systematic review and diagnostic meta-analysis. Data sources Medline, Embase, Cochrane central register of controlled trials, Cochrane database of systematic reviews, database of abstracts of reviews of effects, NHS economic evaluation database, and Health Technology Assessment up to 28 January 2014, using combinations of subject headings and terms relating to heart failure and natriuretic peptides. Eligibility criteria for selecting studies Eligible studies evaluated one or more natriuretic peptides (B type natriuretic peptide, NTproBNP, or MRproANP) in the diagnosis of acute heart failure against an acceptable reference standard in consecutive or randomly selected adults in an acute care setting. Studies were excluded if they did not present sufficient data to extract or calculate true positives, false positives, false negatives, and true negatives, or report age independent natriuretic peptide thresholds. Studies not available in English were also excluded. Results 37 unique study cohorts described in 42 study reports were included, with a total of 48 test evaluations reporting 15 263 test results. At the lower recommended thresholds of 100 ng/L for B type natriuretic peptide and 300 ng/L for NTproBNP, the natriuretic peptides have sensitivities of 0.95 (95% confidence interval 0.93 to 0.96) and 0.99 (0.97 to 1.00) and negative predictive values of 0.94 (0.90 to 0.96) and 0.98 (0.89 to 1.0), respectively, for a diagnosis of acute heart failure. At the lower recommended threshold of 120 pmol/L, MRproANP has a sensitivity ranging from 0.95 (range 0.90-0.98) to 0.97 (0.95-0.98) and a negative predictive value ranging from 0.90 (0.80-0.96) to 0.97 (0.96-0.98). At higher thresholds the sensitivity declined progressively and specificity remained variable across the range of values. There was no statistically significant difference in diagnostic accuracy between plasma B type natriuretic peptide and NTproBNP. Conclusions At the rule-out thresholds recommended in the 2012 European Society of Cardiology guidelines for heart failure, plasma B type natriuretic peptide, NTproBNP, and MRproANP have excellent ability to exclude acute heart failure. Specificity is variable, and so imaging to confirm a diagnosis of heart failure is required. There is no statistical difference between the diagnostic accuracy of plasma B type natriuretic peptide and NTproBNP. Introduction of natriuretic peptide measurement in the investigation of patients with suspected acute heart failure has the potential to allow rapid and accurate exclusion of the diagnosis.

Memantine and cholinesterase inhibitor combination therapy for Alzheimer's disease: a systematic review

Background Memantine is licensed for moderate-to-severe Alzheimers disease (AD). National Institute for Clinical Excellence (NICE) guidance does not recommend the use of memantine in combination with cholinesterase inhibitors (acetylcholinesterase inhibitor (AChEI)). The underpinning meta-analysis was disputed by the manufacturer. Objectives To compare the efficacy of AChEI monotherapy with combination memantine and AChEI therapy in patients with moderate-to-severe AD and to examine the impact of including unpublished data on the results. Design Systematic review and meta-analysis of randomised controlled trials. Data sources The Cochrane Dementia Group trial register, ALOIS, searched for the last time on 3 May 2011. Data synthesis Data from four domains (clinical global, cognition, function, behaviour and mood) were pooled. Sensitivity analyses examined the impact on the NICE-commissioned meta-analysis of restricting data to patients with moderate-to-severe AD and of including an unpublished trial of an extended release preparation of memantine. Results Pooled data from the trials, which were included in the NICE-commissioned meta-analysis but which were restricted to moderate-to-severe AD only, showed a small effect of combination therapy on cognition (standardised mean difference (SMD)=−0.29, 95% CI −0.45 to −0.14). Adding data from an unpublished trial of an extended release memantine (total three trials, 1317 participants) showed a small benefit of combination therapy on global scores (SMD=−0.20, 95% CI −0.31 to −0.09), cognition (SMD=−0.25, 95% CI −0.36 to −0.14) and behaviour and mood (SMD=−0.17, 95% CI −0.32 to −0.03) but not on function (SMD=−0.04, 95% CI −0.21 to 0.13) at 6 months. No clinical data have been reported from a 1-year trial, although this found ‘no significant benefit’ on any clinical measures at 1 year. Conclusions These results suggest that there may be a small benefit at 6 months of adding memantine to AChEIs. However, the impact on clinical global impression depends on exactly which studies are included, and there is no benefit on function, so its clinical relevance is not robustly demonstrated. Currently available information from randomised controlled trails indicates no benefit of combination therapy over monotherapy at 1 year. Legislation on the form and content of registry posted results is needed in Europe.

Mortality of people with chronic fatigue syndrome: a retrospective cohort study in England and Wales from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) Register

BACKGROUND Mortality associated with chronic fatigue syndrome is uncertain. We investigated mortality in individuals diagnosed with chronic fatigue syndrome in secondary and tertiary care using data from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) register. METHODS We calculated standardised mortality ratios (SMRs) for all-cause, suicide-specific, and cancer-specific mortality for a 7-year observation period using the number of deaths observed in SLaM records compared with age-specific and sex-specific mortality statistics for England and Wales. Study participants were included if they had had contact with the chronic fatigue service (referral, discharge, or case note entry) and received a diagnosis of chronic fatigue syndrome. FINDINGS We identified 2147 cases of chronic fatigue syndrome from CRIS and 17 deaths from Jan 1, 2007, to Dec 31, 2013. 1533 patients were women of whom 11 died, and 614 were men of whom six died. There was no significant difference in age-standardised and sex-standardised mortality ratios (SMRs) for all-cause mortality (SMR 1·14, 95% CI 0·65-1·85; p=0·67) or cancer-specific mortality (1·39, 0·60-2·73; p=0·45) in patients with chronic fatigue syndrome when compared with the general population in England and Wales. This remained the case when deaths from suicide were removed from the analysis. There was a significant increase in suicide-specific mortality (SMR 6·85, 95% CI 2·22-15·98; p=0·002). INTERPRETATION We did not note increased all-cause mortality in people with chronic fatigue syndrome, but our findings show a substantial increase in mortality from suicide. This highlights the need for clinicians to be aware of the increased risk of completed suicide and to assess suicidality adequately in patients with chronic fatigue syndrome. FUNDING National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and Kings College London.

Diagnosing and managing acute heart failure in adults: summary of NICE guidance.

Acute heart failure may present de novo in people without known cardiac dysfunction, or as an acute decompensation of known chronic heart failure. Acute heart failure is a common cause of admission to hospital (more than 67 000 admissions in England and Wales each year) and is the leading cause of hospital admission in people aged 65 years or more in the United Kingdom.1 European registry data show that nearly 50% of people admitted to hospital with acute heart failure are re-admitted within 12 months,2 and a third of people with acute heart failure die within a year of their first hospital admission.1 The diagnosis of heart failure can be challenging because of non-specific symptoms and clinical signs, and there is evidence of wide variation in the way people with acute heart failure are managed.1 This article summarises the most recent recommendations from the National Institute for Health and Care Excellence (NICE) on acute heart failure.3 NICE recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations can be based on the Guideline Development Group’s experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Organisation of care

The Representation of Mental Illness in Bermudian Print Media, 1991–2011

OBJECTIVE Stigmatization of persons with mental illness may be perpetuated through media depictions. This study analyzed changes in the depiction of mental illness by Bermudian newspapers over 20 years. METHODS All articles about mental illness in Bermudas newspapers in 1991, 2001, and 2011 (N=277) were coded for composition, language, consultations and quotations, and content. RESULTS A significant increase in mental health professional consultation was demonstrated. Articles with a negative overall tone constituted the largest percentage of all articles (40%) and of articles in 2001 (43%) and 2011 (42%). A significant difference was found in primary theme; between 1991 and 2011, articles with an education and information theme dropped from 40% to 18% and articles about violent crime increased from 12% to 18%. CONCLUSIONS The results may necessitate action from the islands advocacy groups. The findings have implications for discussion with the national press.

The impact of targeted Rheumatoid Arthritis pharmacological treatment on mental health: A systematic review and network meta-analysis.

Rheumatoid arthritis (RA) pharmacotherapy may impact mental health outcomes by improving pain and stiffness, potentially by targeting inflammatory processes common to RA and depression. The objectives of this review were to ascertain the frequency of mental health assessments in RA pharmacotherapy trials, quantify the efficacy of RA pharmacotherapy for mental health outcomes, and explore the clinical and demographic factors related to mental health outcomes. Effective pharmacotherapy alone is unlikely to substantially improve mental health outcomes in most patients with RA. Integrated mental health care provided within routine clinical practice is essential to optimize mental and physical health outcomes.

Caveat emptor: Folate in unipolar depressive illness, a systematic review and meta-analysis:

Background: International guideline recommendations for the use of folate and its derivatives in the treatment of unipolar depressive disorders are confused and contradictory, perhaps reflecting wide variations in the underpinning evidence base. Introduction: We discuss differing methods of evidence synthesis in the formulation of international guideline recommendations. As an example we evaluated the efficacy of folate and its derivatives in unipolar depression via systematic review and meta-analysis. Methods: We searched Medline, EMBASE, PsychInfo and CENTRAL from database inception until 1 May 2017 for randomised controlled trials. We included trials that evaluated folate or its derivatives as monotherapy or to augment antidepressant therapy compared with placebo in patients with unipolar depressive illness. Standardised mean differences were used and studies were introduced as subgroups to explain the heterogeneity. Quality was assessed using the Grading of Recommendations Assessment, Development and Evaluation. Results: No trials report on folate or methylfolate versus placebo as a monotherapeutic option. Only when the evidence was restricted to folate at a dose of <5 mg/day or methylfolate at a dose of 15 mg once daily as an adjunct to selective serotonin reuptake inhibitor therapy was there a significant benefit compared with placebo. All evidence was graded as low or very low quality for each outcome. Discussion: Whilst previous guidelines on the treatment of unipolar depression have either avoided this topic entirely, or made recommendations on the basis of cherry-picked evidence, this review is the first to attempt to provide clinically useful recommendations based on comprehensive, current randomised placebo-controlled data. We invite discussion of the review and its recommendations, which are based on the limited evidence regarding folate formulation delivered and appropriate dosage.

The importance of not jumping to conclusions: syphilis as an organic cause of neurological, psychiatric and endocrine presentations

A 66-year-old Caucasian man was admitted to an acute psychiatric ward under section 2 of the Mental Health Act after presenting with auditory hallucinations and partition delusions. He had been known to mental health services since 2005 but had never been treated with psychotropic medication or given a formal psychiatric diagnosis. He was also diagnosed with hypopituitarism of unknown aetiology in 2002. In light of this presentation, his medical history was reviewed in full, hormone levels and a full delirium screen including blood borne virus and syphilis serology was completed to ensure no organic cause had been missed. The treponemal antibody was positive, and he reported no previous syphilis treatment, as such a diagnosis of neurosyphilis was performed. This case demonstrates a patient presenting with two potential complications of syphilis; psychosis and hypopituitarism where screening for this infection had not been previously considered.

Systematic review of fit note use for workers in the UK

Objectives The fit note, introduced in England, Wales and Scotland in 2010, was designed to change radically the sickness certification process from advising individuals on their inability to work to advising them on what they could do if work could be adapted. Our review aimed to evaluate the following: (1) Is the ‘maybe fit’ for work option being selected for patients? (2) Are work solutions being recommended? (3) Has the fit note increased return to work? (4) Has the fit note reduced the length of sickness absence? We considered the way in which outcomes vary according to patient demographics including type of health problem. Methods Studies were identified by a systematic search. We included all studies of any design conducted in the UK with working age adults, aged 16 or over, from 1 April 2010 to 1 Nov 2017. Risk of bias was assessed using a modified Newcastle-Ottawa Scale. Results Thirteen papers representing seven studies met inclusion criteria. In the largest study, ‘maybe fit’ for work was recommended in 6.5% of fit notes delivered by general practitioners (GP; n=361 801) between April 2016 and March 2017. ‘Maybe fit’ recommendations were made in 8.5%–10% of fit notes received by primary care patients in employment, and in 10%–32% of patients seen by GPs trained in the Diploma in Occupational Medicine. ‘Maybe fit’ was recommended more for women, those with higher socioeconomic status, and for physical, as opposed to psychiatric disorders. The majority of fit notes with the ‘maybe fit’ option selected included work solutions. There was inconclusive evidence to suggest that the introduction of the fit note has reduced sickness absence among patients in employment. Conclusions Fit notes represent a major shift in public policy. Our review suggests that they have been incompletely researched and not implemented as intended.