The quality of paediatric asthma guidelines: evidence underpinning diagnostic test recommendations from a meta-epidemiological study.

BACKGROUND: Asthma is one of the most frequent reasons children visit a general practitioner (GP). The diagnosis of childhood asthma is challenging, and a variety of diagnostic tests for asthma exist. GPs may refer to clinical practice guidelines when deciding which tests, if any, are appropriate, but the quality of these guidelines is unknown. OBJECTIVES: To determine (i) the methodological quality and reporting of paediatric guidelines for the diagnosis of childhood asthma in primary care, and (ii) the strength of evidence supporting diagnostic test recommendations. DESIGN: Meta-epidemiological study of English-language guidelines from the United Kingdom and other high-income countries with comparable primary care systems including diagnostic testing recommendations for childhood asthma in primary care. The AGREE-II tool was used to assess the quality and reporting of the guidelines. The quality of the evidence was assessed using GRADE. RESULTS: Eleven guidelines met the eligibility criteria. The methodology and reporting quality varied across the AGREE II domains (median score 4.5 out of 7, range 2-6). The quality of evidence supporting diagnostic recommendations was generally of very low quality. All guidelines recommended the use of spirometry and reversibility testing for children aged ≥5 years, however, the recommended spirometry thresholds for diagnosis differed across guidelines. There were disagreements in testing recommendations for 3 of the 7 included tests. CONCLUSIONS: The variable quality of guidelines, lack of good quality evidence, and inconsistent recommendations for diagnostic tests may contribute to poor clinician adherence to guidelines and variation in testing for diagnosing childhood asthma.

Factors associated with the prescribing of high-dose opioids in primary care: a systematic review and meta-analysis.

BACKGROUND: The risks of harms from opioids increase substantially at high doses, and high-dose prescribing has increased in primary care. However, little is known about what leads to high-dose prescribing, and studies exploring this have not been synthesized. We, therefore, systematically synthesized factors associated with the prescribing of high-dose opioids in primary care. METHODS: We conducted a systematic review of observational studies in high-income countries that used patient-level primary care data and explored any factor(s) in people for whom opioids were prescribed, stratified by oral morphine equivalents (OME). We defined high doses as ≥ 90 OME mg/day. We searched MEDLINE, Embase, Web of Science, reference lists, forward citations, and conference proceedings from database inception to 5 April 2019. Two investigators independently screened studies, extracted data, and appraised the quality of included studies using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. We pooled data on factors using random effects meta-analyses and reported relative risks (RR) or mean differences with 95% confidence intervals (CI) where appropriate. We also performed a number needed to harm (NNTH) calculation on factors when applicable. RESULTS: We included six studies with a total of 4,248,119 participants taking opioids, of whom 3.64% (n = 154,749) were taking high doses. The majority of included studies (n = 4) were conducted in the USA, one in Australia and one in the UK. The largest study (n = 4,046,275) was from the USA. Included studies were graded as having fair to good quality evidence. The co-prescription of benzodiazepines (RR 3.27, 95% CI 1.32 to 8.13, I2 = 99.9%), depression (RR 1.38, 95% CI 1.27 to 1.51, I2 = 0%), emergency department visits (RR 1.53, 95% CI 1.46 to 1.61, I2 = 0%, NNTH 15, 95% CI 12 to 20), unemployment (RR 1.44, 95% CI 1.27 to 1.63, I2 = 0%), and male gender (RR 1.21, 95% CI 1.14 to 1.28, I2 = 78.6%) were significantly associated with the prescribing of high-dose opioids in primary care. CONCLUSIONS: High doses of opioids are associated with greater risks of harms. Associated factors such as the co-prescription of benzodiazepines and depression identify priority areas that should be considered when selecting, identifying, and managing people taking high-dose opioids in primary care. Coordinated strategies and services that promote the safe prescribing of opioids are needed. STUDY REGISTRATION: PROSPERO, CRD42018088057.

Naltrexone-bupropion (Mysimba) in management of obesity: A systematic review and meta-analysis of unpublished clinical study reports.

AIMS: To compare the benefits and harms of naltrexone-bupropion using evidence from clinical study reports. METHODS: We searched Food and Drug Administration and European Medicines Agency websites, PubMed, and Clinicaltrials.gov (May 2016) to identify pivotal trials; we then sent a freedom of information request to the European Medicines Agency (July 2016). We included pivotal, phase III placebo-controlled trials. We assessed the risks of bias using the Cochrane criteria, and the quality of the evidence using GRADE. We used a random-effects model for meta-analyses. RESULTS: Over a 27-month period (July 2016 to August 2018), we received 31 batches of clinical study report documents containing over 65 000 pages of data from 4 pivotal trials (n = 4536). Significantly more participants who took naltrexone-bupropion achieved ≥5% reduction in body weight: risk ratio (RR) = 2.1 (95% confidence interval 1.35-3.28), P = .001, GRADE = low, number needed to treat (NNT) to benefit = 5 (3-17); this represents a 2.53 kg (1.85-3.21) reduction in baseline body weight compared with placebo. Naltrexone-bupropion had significantly beneficial effects on other cardiovascular risk factors; however, the true effect sizes for these are uncertain because of incomplete outcome data. Naltrexone-bupropion significantly increased the risk of adverse events: RR = 1.11 (1.05-1.18, P = .0004, GRADE = low, NNT to harm = 12 7-27); serious adverse events: RR = 1.70 (1.38-2.1, P < .00001, GRADE = moderate, NNT to harm = 21 13-38); and discontinuation because of adverse events: RR = 1.92 (1.65-2.24, P < .00001, GRADE = moderate, NNT to discontinue treatment = 9 8-13). CONCLUSIONS: Naltrexone-bupropion significantly reduces body weight by a small amount but significantly increases the risk of adverse events. A rigorous process of postmarketing surveillance is required.

Corticosteroids as standalone or add-on treatment for sore throat.

BACKGROUND: Sore throat is a common condition associated with a high rate of antibiotic prescriptions, despite limited evidence for the effectiveness of antibiotics. Corticosteroids may improve symptoms of sore throat by reducing inflammation of the upper respiratory tract. This review is an update to our review published in 2012. OBJECTIVES: To assess the clinical benefit and safety of corticosteroids in reducing the symptoms of sore throat in adults and children. SEARCH METHODS: We searched CENTRAL (Issue 4, 2019), MEDLINE (1966 to 14 May 2019), Embase (1974 to 14 May 2019), the Database of Abstracts of Reviews of Effects (DARE, 2002 to 2015), and the NHS Economic Evaluation Database (inception to 2015). We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared steroids to either placebo or standard care in adults and children (aged over three years) with sore throat. We excluded studies of hospitalised participants, those with infectious mononucleosis (glandular fever), sore throat following tonsillectomy or intubation, or peritonsillar abscess. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included one new RCT in this update, for a total of nine trials involving 1319 participants (369 children and 950 adults). In eight trials, participants in both corticosteroid and placebo groups received antibiotics; one trial offered delayed prescription of antibiotics based on clinical assessment. Only two trials reported funding sources (government and a university foundation). In addition to any effect of antibiotics and analgesia, corticosteroids increased the likelihood of complete resolution of pain at 24 hours by 2.40 times (risk ratio (RR) 2.4, 95% confidence interval (CI) 1.29 to 4.47; P = 0.006; I² = 67%; high-certainty evidence) and at 48 hours by 1.5 times (RR 1.50, 95% CI 1.27 to 1.76; P < 0.001; I² = 0%; high-certainty evidence). Five people need to be treated to prevent one person continuing to experience pain at 24 hours. Corticosteroids also reduced the mean time to onset of pain relief and the mean time to complete resolution of pain by 6 and 11.6 hours, respectively, although significant heterogeneity was present (moderate-certainty evidence). At 24 hours, pain (assessed by visual analogue scales) was reduced by an additional 10.6% by corticosteroids (moderate-certainty evidence). No differences were reported in recurrence/relapse rates, days missed from work or school, or adverse events for participants taking corticosteroids compared to placebo. However, the reporting of adverse events was poor, and only two trials included children or reported days missed from work or school. The included studies were assessed as moderate quality evidence, but the small number of included studies has the potential to increase the uncertainty, particularly in terms of applying these results to children. AUTHORS' CONCLUSIONS: Oral or intramuscular corticosteroids, in addition to antibiotics, moderately increased the likelihood of both resolution and improvement of pain in participants with sore throat. Given the limited benefit, further research into the harms and benefits of short courses of steroids is needed to permit informed decision-making.

Correction to: Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature.

The original article [1] contains a minor error whereby the dates for year of first launch and year of first report of adverse reaction for iophendylate in e-Appendix Table 1 are mistakenly presented as 1946 and 1975 respectively.

Limited evidence for diagnosing bacterial skin infections in older adults in primary care: systematic review.

BACKGROUND: Older adults with bacterial skin infections may present with atypical symptoms, making diagnosis difficult. There is limited authoritative guidance on how older adults in the community present with bacterial skin infections. To date there have been no systematic reviews assessing the diagnostic value of symptoms and signs in identifying bacterial skin infections in older adults in the community. METHODS: We searched Medline and Medline in process, Embase and Web of Science, from inception to September 2017. We included cohort and cross-sectional studies assessing the diagnostic accuracy of symptoms and signs in predicting bacterial skin infections in adults in primary care aged over 65 years. The QUADAS-2 tool was used to assess study quality. RESULTS: We identified two observational studies of low-moderate quality, with a total of 7991 participants, providing data to calculate the diagnostic accuracy of 5 unique symptoms in predicting bacterial skin infections. The presence of wounds [LR+: 7.93 (CI 4.81-13.1)], pressure sores [LR+: 4.85 (CI 2.18-10.8)] and skin ulcers [LR+: 6.26 (CI 5.49-7.13)] help to diagnose bacterial skin infections. The presence of urinary incontinence does not help to predict bacterial skin infections (LR + 's of 0.99 and 1.04; LR-'s of 0.96 and 1.04). CONCLUSIONS: Currently, there is insufficient evidence to inform the diagnosis of bacterial skin infections in older adults in the community; clinicians should therefore rely upon their clinical judgement and experience. Evidence from high quality primary care studies in older adults, including studies assessing symptoms traditionally associated with bacterial skin infections (e.g. erythema and warmth), is urgently needed to guide practice.

Biomarkers for diagnosing serious bacterial infections in older outpatients: a systematic review.

BACKGROUND: The value of biomarkers for diagnosing bacterial infections in older outpatients is uncertain and limited official guidance exists for clinicians in this area. The aim of this review is to critically appraise and evaluate biomarkers for diagnosing bacterial infections in older adults (aged 65 years and above). METHODS: We searched Medline, Embase, Web of Science and the Cochrane Library, from inception to January 2018. We included studies assessing the diagnostic accuracy of blood, urinary, and salivary biomarkers in diagnosing bacterial infections in older adults. The QUADAS-2 tool was used to assess study quality. RESULTS: We identified 11 eligible studies of moderate quality (11,034 participants) including 51 biomarkers at varying thresholds for diagnosing bacterial infections. An elevated Procalcitonin (≥ 0.2 ng/mL) may help diagnose bacteraemia in older adults [+ve LR range 1.50 to 2.60]. A CRP ≥ 50 mg/L only raises the probability of bacteraemia by 5%. A positive urine dipstick aids diagnosis of UTI (+ve LR range 1.23 to 54.90), and absence helps rule out UTI (-ve LR range 0.06 to 0.46). An elevated white blood cell count is unhelpful in diagnosing intra-abdominal infections (+ve LR range 0.75 to 2.62), but may aid differentiation of bacterial infection from other acute illness (+ve LR range 2.14 to 7.12). CONCLUSIONS: The limited available evidence suggests that many diagnostic tests useful in younger patients, do not help to diagnose bacterial infections in older adults. Further evidence from high quality studies is urgently needed to guide clinical practice. Until then, symptoms and signs remain the mainstay of diagnosis in community based populations.

Postmarketing withdrawal of human medicinal products because of adverse reactions in animals: a systematic review and analysis.

PURPOSE: We have identified human medicinal products for which animal data were used as evidence for withdrawal, determined whether the adverse reactions were reported in humans, established whether confirmatory human studies were conducted, and explored the withdrawal patterns over time. METHODS: We searched the World Health Organization's Consolidated List of [Medicinal] Products, drug regulatory authorities' websites, PubMed, Google Scholar, and selected textbooks to identify medicinal products withdrawn from 1950 to June 2016. We included medicinal products for which animal data were specifically reported as a reason for withdrawal. We used a checklist adapted from the International Agency for Research on Cancer criteria to rate the evidence. RESULTS: In 37 cases, evidence from animals was the reason given for withdrawal between 1963 and 2000. Evidence of carcinogenicity was cited in 23 cases (62%). Limited evidence for harms occasioned withdrawal in over 80% of cases. In 11 cases (30%), the adverse drug reactions were subsequently reported in humans. In 5 instances (14%), formal studies were conducted in humans. The median interval to withdrawal following reports of adverse reactions was 2 years (IQR = 1-9 y). CONCLUSIONS: Regulatory authorities and drug manufacturers are likely to withdraw medicinal products quickly from the market when animal experiments suggest increased risks of cancers or congenital malformations. Human studies are seldom conducted when harms are suspected in animals. Future research should explore better methods of extrapolating harms data from animal research to humans.

The efficacy of supplementation with the novel medical food, Souvenaid, in patients with Alzheimer's disease: A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND AND RATIONALE: Certain nutritional supplements are being marketed for the management of Alzheimer's disease (AD), but the evidence for their effectiveness is not established. The objective of this review was to evaluate the evidence from randomized clinical trial (RCTs) examining the effect of Souvenaid in patients with AD. METHODS: We conducted electronic searches in Medline, Embase, PsychINFO, CINAHL, and The Cochrane Library. The reporting quality of the included studies was determined using the Cochrane collaboration tool for assessing the risk of bias. Two reviewers independently determined eligibility, assessed the reporting quality of included studies and extracted data. RESULTS: Three studies with a total of 1011 participants were included. All were of good reporting quality. Meta-analyses revealed non-significant differences in cognition (ADAS-cog scores MD: 0.08, 95% CI: -0.71 to 0.88) and function (ADCS-ADL scores MD: 0.36, 95% CI: -0.54 to 1.25) between Souvenaid and placebo. One study showed significant increase in neuropsychological test battery composite z-score with Souvenaid compared with placebo, and another reported significant improvement in delayed verbal recall for a subgroup of patients with very mild AD. There was no significant effect on global clinical function. No serious adverse events were observed. CONCLUSIONS: The evidence from published clinical trials does not show that supplementation with Souvenaid has beneficial effects on functional ability, behaviour, or global clinical change. Souvenaid may cause improvements in verbal recall in patients at early stages of AD. Few RCTs examining the effect of Souvenaid have been conducted, and they are all funded by same manufacturer. Future research should include using unified tools to measure cognition, function, and behaviour in AD.

Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature.

BACKGROUND: There have been no studies of the patterns of post-marketing withdrawals of medicinal products to which adverse reactions have been attributed. We identified medicinal products that were withdrawn because of adverse drug reactions, examined the evidence to support such withdrawals, and explored the pattern of withdrawals across countries. METHODS: We searched PubMed, Google Scholar, the WHO's database of drugs, the websites of drug regulatory authorities, and textbooks. We included medicinal products withdrawn between 1950 and 2014 and assessed the levels of evidence used in making withdrawal decisions using the criteria of the Oxford Centre for Evidence Based Medicine. RESULTS: We identified 462 medicinal products that were withdrawn from the market between 1953 and 2013, the most common reason being hepatotoxicity. The supporting evidence in 72 % of cases consisted of anecdotal reports. Only 43 (9.34 %) drugs were withdrawn worldwide and 179 (39 %) were withdrawn in one country only. Withdrawal was significantly less likely in Africa than in other continents (Europe, the Americas, Asia, and Australasia and Oceania). The median interval between the first reported adverse reaction and the year of first withdrawal was 6 years (IQR, 1-15) and the interval did not consistently shorten over time. CONCLUSION: There are discrepancies in the patterns of withdrawal of medicinal products from the market when adverse reactions are suspected, and withdrawals are inconsistent across countries. Greater co-ordination among drug regulatory authorities and increased transparency in reporting suspected adverse drug reactions would help improve current decision-making processes.

Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review.

BACKGROUND: We identified anti-obesity medications withdrawn since 1950 because of adverse drug reactions after regulatory approval, and examined the evidence used to support such withdrawals, investigated the mechanisms of the adverse reactions, and explored the trends over time. METHODS: We conducted searches in PubMed, the World Health Organization database of drugs, the websites of drug regulatory authorities, and selected full texts, and we hand searched references in retrieved documents. We included anti-obesity medications that were withdrawn between 1950 and December 2015 and assessed the levels of evidence used for making withdrawal decisions using the Oxford Centre for Evidence-Based Medicine criteria. RESULTS: We identified 25 anti-obesity medications withdrawn between 1964 and 2009; 23 of these were centrally acting, via monoamine neurotransmitters. Case reports were cited as evidence for withdrawal in 80% of instances. Psychiatric disturbances, cardiotoxicity (mainly attributable to re-uptake inhibitors), and drug abuse or dependence (mainly attributable to neurotransmitter releasing agents) together accounted for 83% of withdrawals. Deaths were reportedly associated with seven products (28%). In almost half of the cases, the withdrawals occurred within 2 years of the first report of an adverse reaction. CONCLUSIONS: Most of the drugs that affect monoamine neurotransmitters licensed for the treatment of obesity over the past 65 years have been withdrawn because of adverse reactions. The reasons for withdrawal raise concerns about the wisdom of using pharmacological agents that target monoamine neurotransmitters in managing obesity. Greater transparency in the assessment of harms from anti-obesity medications is therefore warranted.

Worldwide withdrawal of medicinal products because of adverse drug reactions: a systematic review and analysis.

We have systematically identified medicinal products withdrawn worldwide because of adverse drug reactions, assessed the level of evidence used for making the withdrawal decisions, and explored the patterns of withdrawals over time. We searched PubMed, the WHO database of withdrawn products, and selected texts. We included products that were withdrawn after launch from 1950 onwards, excluding non-human and over-the-counter medicines. We assessed the levels of evidence on which withdrawals were based using the Oxford Center for Evidence Based Medicine Levels of Evidence. Of 353 medicinal products withdrawn from any country, only 40 were withdrawn worldwide. Anecdotal reports were cited as evidence for withdrawal in 30 (75%) and deaths occurred in 27 (68%). Hepatic, cardiac, and nervous system toxicity accounted for over 60% of withdrawals. In 28 cases, the first withdrawal was initiated by the manufacturer. The median interval between the first report of an adverse drug reaction that led to withdrawal and the first withdrawal was 1 year (range 0-43 years). Worldwide withdrawals occurred within 1 year after the first withdrawal in any country. In conclusion, the time it takes for drugs to be withdrawn worldwide after reports of adverse drug reactions has shortened over time. However, there are inconsistencies in current withdrawal procedures when adverse drug reactions are suspected. A uniform method for establishing worldwide withdrawal of approved medicinal products when adverse drug reactions are suspected should be developed, to facilitate global withdrawals. Rapid synthesis of the evidence on harms should be a priority when serious adverse reactions are suspected.

Self-monitoring and self-management of oral anticoagulation.

BACKGROUND: The introduction of point-of-care devices for the management of patients on oral anticoagulation allows self-testing by the patient at home. Patients who self-test can either adjust their medication according to a pre-determined dose-INR (international normalized ratio) schedule (self-management), or they can call a clinic to be told the appropriate dose adjustment (self-monitoring). Increasing evidence suggests self-testing of oral anticoagulant therapy is equal to or better than standard monitoring. This is an updated version of the original review published in 2010. OBJECTIVES: To evaluate the effects on thrombotic events, major haemorrhages, and all-cause mortality of self-monitoring or self-management of oral anticoagulant therapy compared to standard monitoring. SEARCH METHODS: For this review update, we re-ran the searches of the Cochrane Central Register of Controlled Trials (CENTRAL), 2015, Issue 6, the Cochrane Library, MEDLINE (Ovid, 1946 to June week 4 2015), Embase (Ovid, 1980 to 2015 week 27) on 1 July 2015. We checked bibliographies and contacted manufacturers and authors of relevant studies. We did not apply any language restrictions . SELECTION CRITERIA: Outcomes analysed were thromboembolic events, mortality, major haemorrhage, minor haemorrhage, tests in therapeutic range, frequency of testing, and feasibility of self-monitoring and self-management. DATA COLLECTION AND ANALYSIS: Review authors independently extracted data and we used a fixed-effect model with the Mantzel-Haenzel method to calculate the pooled risk ratio (RR) and Peto's method to verify the results for uncommon outcomes. We examined heterogeneity amongst studies with the Chi(2) and I(2) statistics and used GRADE methodology to assess the quality of evidence. MAIN RESULTS: We identified 28 randomised trials including 8950 participants (newly incorporated in this update: 10 trials including 4227 participants). The overall quality of the evidence was generally low to moderate. Pooled estimates showed a reduction in thromboembolic events (RR 0.58, 95% CI 0.45 to 0.75; participants = 7594; studies = 18; moderate quality of evidence). Both, trials of self-management or self-monitoring showed reductions in thromboembolic events (RR 0.47, 95% CI 0.31 to 0.70; participants = 3497; studies = 11) and (RR 0.69, 95% CI 0.49 to 0.97; participants = 4097; studies = 7), respectively; the quality of evidence for both interventions was moderate. No reduction in all-cause mortality was found (RR 0.85, 95% CI 0.71 to 1.01; participants = 6358; studies = 11; moderate quality of evidence). While self-management caused a reduction in all-cause mortality (RR 0.55, 95% CI 0.36 to 0.84; participants = 3058; studies = 8); self-monitoring did not (RR 0.94, 95% CI 0.78 to 1.15; participants = 3300; studies = 3); the quality of evidence for both interventions was moderate. In 20 trials (8018 participants) self-monitoring or self-management did not reduce major haemorrhage (RR 0.95, 95% CI, 0.80 to 1.12; moderate quality of evidence). There was no significant difference found for minor haemorrhage (RR 0.97, 95% CI 0.67 to 1.41; participants = 5365; studies = 13). The quality of evidence was graded as low because of serious risk of bias and substantial heterogeneity (I(2) = 82%). AUTHORS' CONCLUSIONS: Participants who self-monitor or self-manage can improve the quality of their oral anticoagulation therapy. Thromboembolic events were reduced, for both those self-monitoring or self-managing oral anticoagulation therapy. A reduction in all-cause mortality was observed in trials of self-management but not in self-monitoring, with no effects on major haemorrhage.

B-type natriuretic peptide-guided treatment for heart failure.

BACKGROUND: Heart failure is a condition in which the heart does not pump enough blood to meet all the needs of the body. Symptoms of heart failure include breathlessness, fatigue and fluid retention. Outcomes for patients with heart failure are highly variable; however on average, these patients have a poor prognosis. Prognosis can be improved with early diagnosis and appropriate use of medical treatment, use of devices and transplantation. Patients with heart failure are high users of healthcare resources, not only due to drug and device treatments, but due to high costs of hospitalisation care. B-type natriuretic peptide levels are already used as biomarkers for diagnosis and prognosis of heart failure, but could offer to clinicians a possible tool to guide drug treatment. This could optimise drug management in heart failure patients whilst allaying concerns over potential side effects due to drug intolerance. OBJECTIVES: To assess whether treatment guided by serial BNP or NT-proBNP (collectively referred to as NP) monitoring improves outcomes compared with treatment guided by clinical assessment alone. SEARCH METHODS: Searches were conducted up to 15 March 2016 in the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (OVID), Embase (OVID), the Database of Abstracts of Reviews of Effects (DARE) and the NHS Economic Evaluation Database in the Cochrane Library. Searches were also conducted in the Science Citation Index Expanded, the Conference Proceedings Citation Index on Web of Science (Thomson Reuters), World Health Organization International Clinical Trials Registry and ClinicalTrials.gov. We applied no date or language restrictions. SELECTION CRITERIA: We included randomised controlled trials of NP-guided treatment of heart failure versus treatment guided by clinical assessment alone with no restriction on follow-up. Adults treated for heart failure, in both in-hospital and out-of-hospital settings, and trials reporting a clinical outcome were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted data and evaluated risk of bias. Risk ratios (RR) were calculated for dichotomous data, and pooled mean differences (MD) (with 95% confidence intervals (CI)) were calculated for continuous data. We contacted trial authors to obtain missing data. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, we assessed the quality of the evidence and GRADE profiler (GRADEPRO) was used to import data from Review Manager to create a 'Summary of findings' table. MAIN RESULTS: We included 18 randomised controlled trials with 3660 participants (range of mean age: 57 to 80 years) comparing NP-guided treatment with clinical assessment alone. The evidence for all-cause mortality using NP-guided treatment showed uncertainty (RR 0.87, 95% CI 0.76 to 1.01; patients = 3169; studies = 15; low quality of the evidence), and for heart failure mortality (RR 0.84, 95% CI 0.54 to 1.30; patients = 853; studies = 6; low quality of evidence).The evidence suggested heart failure admission was reduced by NP-guided treatment (38% versus 26%, RR 0.70, 95% CI 0.61 to 0.80; patients = 1928; studies = 10; low quality of evidence), but the evidence showed uncertainty for all-cause admission (57% versus 53%, RR 0.93, 95% CI 0.84 to 1.03; patients = 1142; studies = 6; low quality of evidence).Six studies reported on adverse events, however the results could not be pooled (patients = 1144; low quality of evidence). Only four studies provided cost of treatment results, three of these studies reported a lower cost for NP-guided treatment, whilst one reported a higher cost (results were not pooled; patients = 931, low quality of evidence). The evidence showed uncertainty for quality of life data (MD -0.03, 95% CI -1.18 to 1.13; patients = 1812; studies = 8; very low quality of evidence).We completed a 'Risk of bias' assessment for all studies. The impact of risk of bias from lack of blinding of outcome assessment and high attrition levels was examined by restricting analyses to only low 'Risk of bias' studies. AUTHORS' CONCLUSIONS: In patients with heart failure low-quality evidence showed a reduction in heart failure admission with NP-guided treatment while low-quality evidence showed uncertainty in the effect of NP-guided treatment for all-cause mortality, heart failure mortality, and all-cause admission. Uncertainty in the effect was further shown by very low-quality evidence for patient's quality of life. The evidence for adverse events and cost of treatment was low quality and we were unable to pool results.

Delays in the post-marketing withdrawal of drugs to which deaths have been attributed: a systematic investigation and analysis.

BACKGROUND: Post-marketing withdrawal of medicinal products because of deaths can be occasioned by evidence obtained from case reports, observational studies, randomized trials, or systematic reviews. There have been no studies of the pattern of withdrawals of medicinal products to which deaths have been specifically attributed and the evidence that affects such decisions. Our objectives were to identify medicinal products that were withdrawn after marketing in association with deaths, to search for the evidence on which withdrawal decisions were based, and to analyse the delays involved and the worldwide patterns of withdrawal. METHODS: We searched the World Health Organization's Consolidated List of [Medicinal] Products, drug regulatory authorities' websites, PubMed, Google Scholar, and textbooks on adverse drug reactions. We included medicinal products for which death was specifically mentioned as a reason for withdrawal from the market. Non-human medicines, herbal products, and non-prescription medicines were excluded. One reviewer extracted the data and a second reviewer verified them independently. RESULTS: We found 95 drugs for which death was documented as a reason for withdrawal between 1950 and 2013. All were withdrawn in at least one country, but at least 16 remained on the market in some countries. Withdrawals were more common in European countries; few were recorded in Africa (5.3%). The more recent the launch date, the sooner deaths were reported. However, in 47% of cases more than 2 years elapsed between the first report of a death and withdrawal of the drug, and the interval between the first report of a death attributed to a medicinal product and eventual withdrawal of the product has not improved over the last 60 years. CONCLUSIONS: These results suggest that some deaths associated with these products could have been avoided. Manufacturers and regulatory authorities should expedite investigations when deaths are reported as suspected adverse drug reactions and consider early suspensions. Increased transparency in the publication of clinical trials data and improved international co-ordination could shorten the delays in withdrawing dangerous medicinal products after reports of deaths and obviate discrepancies in drug withdrawals in different countries.

Antibiotics for preventing lower respiratory tract infections in high-risk children aged 12 years and under.

BACKGROUND: Lower respiratory tract infections (LRTIs) in young children account for 1.4 million deaths annually worldwide. Antibiotics could be beneficial in preventing LRTIs in high-risk children, and may also help prevent school absenteeism and work days missed by children and/or carers. While it is well documented that the efficacy of antibiotic prophylaxis for RTIs decreases over time, there are no reviews that describe the use of antibiotic prophylaxis to prevent LRTIs in high-risk children aged 12 years and under. OBJECTIVES: To assess the effectiveness and safety of antibiotic prophylaxis in the prevention of bacterial LRTIs in high-risk children aged 12 years and under. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 1) and the Database of Abstracts of Reviews of Effects (DARE), MEDLINE and MEDLINE In-Process (OvidSP) (1946 to 13 February 2015), EMBASE (OvidSP) (1974 to 12 February 2015), Science Citation Index Expanded (1945 to 13 February 2015) and Conference Proceedings Citation Index-Science (Web of Science Core Collection) (1990 to 13 February 2015). We searched for ongoing studies on ClinicalTrials.gov and the World Health Organization ICTRP. We handsearched the bibliographies of retrieved full texts of relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing oral or intravenous antibiotics versus placebo or no treatment to prevent infections in high-risk children aged 12 years and under. We used a combination of the Centers for Disease Control and Prevention (CDC), National Health Service (NHS), American Academy of Paediatrics (AAP) and National Institute for Health and Care Excellence (NICE) guidelines to define conditions at higher risk of complications. Our primary outcome was the incidence of bacterial lower respiratory infections. Secondary outcomes included clinical function, hospital admission, mortality, growth, use of secondary antibiotics, time off school or parental work, quality of life and adverse events. DATA COLLECTION AND ANALYSIS: We extracted data using a customised data extraction sheet, assessed the risk of bias of included studies using the Cochrane 'Risk of bias' criteria, and used the GRADE criteria to rate the quality of the evidence. We used a random-effects model for meta-analysis. We presented the results narratively where we could not statistically combine data. MAIN RESULTS: We included 10 RCTs of high-risk children using antibiotics (azithromycin, ciprofloxacin, co-trimoxazole, isoniazid, oral penicillin V or vancomycin) to prevent LRTIs. Three studies included HIV-infected children (n = 1345), four cystic fibrosis (n = 429) and one each sickle cell disease (n = 219), cancer (n = 160) and low birth weight neonates with underlying respiratory disorders (n = 40). The study duration ranged from seven days to three years. The quality of the evidence from studies including children with HIV infection, cystic fibrosis or cancer was moderate. Due to inadequate data, we were unable to rate the quality of the evidence for two studies: one in children with sickle cell disease (low risk of bias), and another in low birth weight neonates with underlying respiratory disorders (high risk of bias).In HIV-infected children receiving continuous isoniazid prophylaxis, there was no significant difference in the incidence of pulmonary tuberculosis (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.32 to 1.29, I(2) statistic = 47%, P value = 0.21). There was no significant effect on mortality with co-trimoxazole or isoniazid prophylaxis (RR 0.82, 0.46 to 1.46, I(2) statistic = 76%, P value = 0.58); however, analysis of one study that used co-trimoxazole showed a significant reduction in mortality (RR 0.67, 95% CI 0.53 to 0.85, P value = 0.001). There was a significant decrease in the rates of hospital admission per child-year of follow-up with co-trimoxazole prophylaxis in one study (P value = 0.01). There was no evidence of increased adverse events due to antibiotic prophylaxis (RR 1.10, 95% CI 0.75 to 1.64, I(2) statistic = 22%, P value = 0.28); however, there was scant reporting of antibiotic resistance - the one study that did assess this found no increase.In two studies of children with cystic fibrosis receiving ciprofloxacin prophylaxis, there was no significant difference in Pseudomonas infections (RR 0.76, 0.44 to 1.31, I(2) statistic = 0%, P value = 0.33). In two studies assessing the benefit of azithromycin prophylaxis, there was a significant reduction in the frequency of pulmonary exacerbations (RR 0.60, 95% CI 0.48 to 0.76, I(2) statistic = 0%, P value < 0.0001). The effect of antibiotic prophylaxis on growth in children with cystic fibrosis was inconsistent across the studies. There was an increased risk of emergence of pathogenic strains with either azithromycin or ciprofloxacin prophylaxis in two studies reporting this outcome. There was no significant difference in the quality of life (one study). In three studies, there was no significant increase in the frequency of adverse events with prophylaxis with azithromycin (two studies) or ciprofloxacin (one study). There was no evidence of increased antibiotic resistance in two studies.In the one study of children with sickle cell disease, a significantly lesser proportion of children with pneumococcal septicaemia was reported with penicillin V prophylaxis (P value = 0.0025).In the one study of children with cancer there was a significant decrease in Pneumocystis carinii pneumonia with trimethoprim-sulfamethoxazole prophylaxis (RR 0.03, 95% CI 0.00 to 0.47, P value < 0.01). There was no significant increase in the frequency of adverse events with antibiotic prophylaxis.In low birth weight children with underlying respiratory disorders, there was no significant difference in the proportion of children with pulmonary infection with vancomycin prophylaxis (P value = 0.18).No included studies reported time off school or carer time off work. AUTHORS' CONCLUSIONS: There is inconclusive evidence that antibiotic prophylaxis in certain groups of high-risk children can reduce pneumonia, exacerbations, hospital admission and mortality in certain conditions. However, limitations in the evidence base mean more clinical trials assessing the effectiveness of antibiotics for preventing LRTIs in children at high risk should be conducted. Specifically, clinical trials assessing the effectiveness of antibiotics for preventing LRTIs in congenital heart disease, metabolic disease, endocrine and renal disorders, neurological disease or prematurity should be a priority.

Email for clinical communication between healthcare professionals.

BACKGROUND: Email is one of the most widely used methods of communication, but its use in healthcare is still uncommon. Where email communication has been utilised in health care, its purposes have included clinical communication between healthcare professionals, but the effects of using email in this way are not well known. We updated a 2012 review of the use of email for two-way clinical communication between healthcare professionals. OBJECTIVES: To assess the effects of email for clinical communication between healthcare professionals on healthcare professional outcomes, patient outcomes, health service performance, and service efficiency and acceptability, when compared to other forms of communicating clinical information. SEARCH METHODS: We searched: the Cochrane Consumers and Communication Review Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 9 2013), MEDLINE (OvidSP) (1946 to August 2013), EMBASE (OvidSP) (1974 to August 2013), PsycINFO (1967 to August 2013), CINAHL (EbscoHOST) (1982 to August 2013), and ERIC (CSA) (1965 to January 2010). We searched grey literature: theses/dissertation repositories, trials registers and Google Scholar (searched November 2013). We used additional search methods: examining reference lists and contacting authors. SELECTION CRITERIA: Randomised controlled trials, quasi-randomised trials, controlled before and after studies, and interrupted time series studies examining interventions in which healthcare professionals used email for communicating clinical information in the form of: 1) unsecured email, 2) secure email, or 3) web messaging. All healthcare professionals, patients and caregivers in all settings were considered. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion, assessed the included studies' risk of bias, and extracted data. We contacted study authors for additional information and have reported all measures as per the study report. MAIN RESULTS: The previous version of this review included one randomised controlled trial involving 327 patients and 159 healthcare providers at baseline. It compared an email to physicians containing patient-specific osteoporosis risk information and guidelines for evaluation and treatment versus usual care (no email). This study was at high risk of bias for the allocation concealment and blinding domains. The email reminder changed health professional actions significantly, with professionals more likely to provide guideline-recommended osteoporosis treatment (bone density measurement or osteoporosis medication, or both) when compared with usual care. The evidence for its impact on patient behaviours or actions was inconclusive. One measure found that the electronic medical reminder message impacted patient behaviour positively (patients had a higher calcium intake), and two found no difference between the two groups. The study did not assess health service outcomes or harms.No new studies were identified for this update. AUTHORS' CONCLUSIONS: Only one study was identified for inclusion, providing insufficient evidence for guiding clinical practice in regard to the use of email for clinical communication between healthcare professionals. Future research should aim to utilise high-quality study designs that use the most recent developments in information technology, with consideration of the complexity of email as an intervention.

Corticosteroids for the common cold.

BACKGROUND: The common cold is a frequent illness, which, although benign and self limiting, results in many consultations to primary care and considerable loss of school or work days. Current symptomatic treatments have limited benefit. Corticosteroids are an effective treatment in other upper respiratory tract infections and their anti-inflammatory effects may also be beneficial in the common cold. This updated review has included one additional study. OBJECTIVES: To compare corticosteroids versus usual care for the common cold on measures of symptom resolution and improvement in children and adults. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 4), which includes the Acute Respiratory Infections (ARI) Group's Specialised Register, the Database of Reviews of Effects (DARE) (2015, Issue 2), NHS Health Economics Database (2015, Issue 2), MEDLINE (1948 to May week 3, 2015) and EMBASE (January 2010 to May 2015). SELECTION CRITERIA: Randomised, double-blind, controlled trials comparing corticosteroids to placebo or to standard clinical management. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. We were unable to perform meta-analysis and instead present a narrative description of the available evidence. MAIN RESULTS: We included three trials (353 participants). Two trials compared intranasal corticosteroids to placebo and one trial compared intranasal corticosteroids to usual care; no trials studied oral corticosteroids. In the two placebo-controlled trials, no benefit of intranasal corticosteroids was demonstrated for duration or severity of symptoms. The risk of bias overall was low or unclear in these two trials. In a trial of 54 participants, the mean number of symptomatic days was 10.3 in the placebo group, compared to 10.7 in those using intranasal corticosteroids (P value = 0.72). A second trial of 199 participants reported no significant differences in the duration of symptoms. The single-blind trial in children aged two to 14 years, who were also receiving oral antibiotics, had inadequate reporting of outcome measures regarding symptom resolution. The overall risk of bias was high for this trial. Mean symptom severity scores were significantly lower in the group receiving intranasal steroids in addition to oral amoxicillin. One placebo-controlled trial reported the presence of rhinovirus in nasal aspirates and found no differences. Only one of the three trials reported on adverse events; no differences were found. Two trials reported secondary bacterial infections (one case of sinusitis, one case of acute otitis media; both in the corticosteroid groups). A lack of comparable outcome measures meant that we were unable to combine the data. AUTHORS' CONCLUSIONS: Current evidence does not support the use of intranasal corticosteroids for symptomatic relief from the common cold. However, there were only three trials, one of which was very poor quality, and there was limited statistical power overall. Further large, randomised, double-blind, placebo-controlled trials in adults and children are required to answer this question.

Vitamin K for improved anticoagulation control in patients receiving warfarin.

BACKGROUND: Effective use of warfarin involves keeping the international normalised ratio (INR) within a relatively narrow therapeutic range. However, patients respond widely to their dose of warfarin. Overcoagulation can lead to an increased risk of excessive bleeding, while undercoagulation can lead to increased clot formation. There is some evidence that patients with a variable response to warfarin may benefit from a concomitant low dose of vitamin K. OBJECTIVES: To assess the effects of concomitant supplementation of low-dose oral vitamin K for anticoagulation control in patients being initiated on or taking a maintenance dose of warfarin. SEARCH METHODS: To identify previous reviews, we searched the Database of Abstracts of Reviews of Effects (DARE via The Cochrane Library, Wiley) (Issue 2, 2011). To identify primary studies, we searched the Cochrane Central Register of Controlled Trials (CENTRAL via The Cochrane Library, Wiley) (Issue 2, 2014), Ovid MEDLINE (R) In-Process & Other Non-Indexed Citations database and Ovid MEDLINE (R) (OvidSP) (1946 to 25 February 2014), Embase (OvidSP) (1974 to week 8 of 2014), Science Citation Index Expanded™ & Conference Proceedings Citation Index - Science (Web of Science™) (1945 to 27 February 2014), and the NHS Economics Evaluations Database (NHS EED) (via The Cochrane Library, Wiley) (Issue 2, 2014). We did not apply any language or date restrictions. We used additional methods to identify grey literature and ongoing studies. SELECTION CRITERIA: Randomised controlled trials comparing the addition of vitamin K versus placebo in patients initiating warfarin or already taking warfarin. DATA COLLECTION AND ANALYSIS: Two review authors independently selected and extracted data from included studies. When disagreement arose, a third author helped reached a consensus. We also assessed risk of bias. MAIN RESULTS: We identified two studies with a total of 100 participants for inclusion in the review. We found the overall risk of bias to be unclear in a number of domains. Neither study reported the time taken to the first INR in range. Only one study (70 participants) reported the mean time in therapeutic range as a percentage. This study found that in the group of participants deemed to have poor INR control, the addition of 150 micrograms (mcg) oral vitamin K significantly improved anticoagulation control in those with unexplained instability of response to warfarin. The second study (30 participants) reported the effect of 175 mcg oral vitamin K versus placebo on participants with high variability in their INR levels. The study concluded that vitamin K supplementation did not significantly improve the stability of anticoagulation for participants on chronic anticoagulation therapy. However, the study was only available in abstract form, and communication with the lead author confirmed that there were no further publications. Therefore, we interpreted this conclusion with caution. Neither study reported any thromboembolic events, haemorrhage, or death from the addition of vitamin K supplementation. AUTHORS' CONCLUSIONS: Two included studies in this review compared whether the addition of a low dose (150 to 175 mcg) of vitamin K given to participants with a high-variability response to warfarin improved their INR control. One study demonstrated a significant improvement, while another smaller study (published in abstract only) suggested no overall benefit. Currently, there are insufficient data to suggest an overall benefit. Larger, higher quality trials are needed to examine if low-dose vitamin K improves INR control in those starting or already taking warfarin.