Calcium hydroxide as an intracanal medication for postoperative pain during primary root canal therapy: A systematic review and meta-analysis with trial sequential analysis of randomised controlled trials.

OBJECTIVE: To evaluate the effectiveness of CH as an intracanal medicament compared to no dressing and / or other intracanal medicaments to control postoperative pain in patients with apical periodontitis requiring primary root canal therapy. MATERIALS AND METHODS: We conducted electronic searches in PubMed, EMBASE, Scopus and Cochrane Library, Open Gray, and Google Scholar. A structured Population-Intervention-Comparison-Outcome of the review was as follows: Population: adults who presented with apical periodontitis requiring primary root canal therapy; Intervention: CH intracanal medicament; Comparison: no dressing/other intracanal medicaments; Main Outcome: Postoperative pain. We assessed the risk of bias using Cochrane criteria. Our outcome measures were intensity of pain on a validated scale reported as mean and standard deviation. We performed meta-analysis using the random-effects model. We rated the quality of evidence using GRADE. RESULTS: We included 18 studies with 1192 participants. The overall risk of bias was moderate. We found a significant improvement in postoperative pain at 24 hours in favor of CH over no intracanal medication (4 trials, n = 226: standardised mean difference: -0.71; [95% confidence interval: -1.38, -0.03]; P = .04; I2= 78%; moderate certainty evidence). Ledermix (Lederle Germany) (steroid-antibiotic) and chlorhexidine were significantly more effective than CH for controlling pain at 72 hours postprocedure (low certainty evidence). Silver nanoparticles were more effective than CH at 6 and 24 hours and combinations of CH with dexamethasone or lidocaine HCl were significantly more effective than CH alone at improving postoperative pain. Substantial heterogeneity limits the robustness of findings. CONCLUSION: Limited evidence suggests that CH may be an effective intracanal medicament for controlling interappointment pain. Combination therapies appear to be more effective than using CH alone. Further research assessing the comparative effectiveness of interventions for managing postoperative pain following root canal therapy is warranted.

Effect of Behavior Change Techniques Targeting Clinicians to Improve Advance Care Planning in Heart Failure: A Systematic Review and Meta-Analysis.

BACKGROUND: National and international guidelines recommend advance care planning (ACP) for patients with heart failure. But clinicians seem hesitant to engage with ACP. PURPOSE: Our aim was to identify behavioral interventions with the greatest potential to engage clinicians with ACP in heart failure. METHODS: A systematic review and meta-analysis. We searched CINAHL, Cochrane Central Register of Controlled Trials, Database of Systematic Reviews, Embase, ERIC, Ovid MEDLINE, Science Citation Index, and PsycINFO for randomized controlled trials (RCTs) from inception to August 2018. Three reviewers independently extracted data, assessed risk of bias (Cochrane risk of bias tool), the quality of evidence (Grading of Recommendation Assessment, Development, and Evaluation), and intervention synergy according to the behavior change wheel and behavior change techniques (BCTs). Odds ratios (ORs) were calculated for pooled effects. RESULTS: Of 14,483 articles screened, we assessed the full text of 131 studies. Thirteen RCTs including 3,709 participants met all of the inclusion criteria. The BCTs of prompts/cues (OR: 4.18; 95% confidence interval [CI]: 2.03-8.59), credible source (OR: 3.24; 95% CI: 1.44-7.28), goal setting (outcome; OR: 2.67; 95% CI: 1.56-4.57), behavioral practice/rehearsal (OR: 2.64; 95% CI: 1.50-4.67), instruction on behavior performance (OR: 2.49; 95% CI: 1.63-3.79), goal setting (behavior; OR: 2.12; 95% CI: 1.57-2.87), and information about consequences (OR: 2.06; 95% CI: 1.40-3.05) showed statistically significant effects to engage clinicians with ACP. CONCLUSION: Certain BCTs seem to improve clinicians' practice with ACP in heart failure and merit consideration for implementation into routine clinical practice.

The Effect of Advance Care Planning on Heart Failure: a Systematic Review and Meta-analysis.

BACKGROUND: Advance care planning is widely advocated to improve outcomes in end-of-life care for patients suffering from heart failure. But until now, there has been no systematic evaluation of the impact of advance care planning (ACP) on clinical outcomes. Our aim was to determine the effect of ACP in heart failure through a meta-analysis of randomized controlled trials (RCTs). METHODS: We searched CINAHL, Cochrane Central Register of Controlled Trials, Database of Systematic Reviews, Embase, ERIC, Ovid MEDLINE, Science Citation Index and PsycINFO (inception to July 2018). We selected RCTs including adult patients with heart failure treated in a hospital, hospice or community setting. Three reviewers independently screened studies, extracted data, assessed the risk of bias (Cochrane risk of bias tool) and evaluated the quality of evidence (GRADE tool) and analysed interventions according to the Template for Intervention Description and Replication (TIDieR). We calculated standardized mean differences (SMD) in random effects models for pooled effects using the generic inverse variance method. RESULTS: Fourteen RCTs including 2924 participants met all of the inclusion criteria. There was a moderate effect in favour of ACP for quality of life (SMD, 0.38; 95% CI [0.09 to 0.68]), patients' satisfaction with end-of-life care (SMD, 0.39; 95% CI [0.14 to 0.64]) and the quality of end-of-life communication (SMD, 0.29; 95% CI [0.17 to 0.42]) for patients suffering from heart failure. ACP seemed most effective if it was introduced at significant milestones in a patient's disease trajectory, included family members, involved follow-up appointments and considered ethnic preferences. Several sensitivity analyses confirmed the statistically significant direction of effect. Heterogeneity was mainly due to different study settings, length of follow-up periods and compositions of ACP. CONCLUSIONS: ACP improved quality of life, patient satisfaction with end-of-life care and the quality of end-of-life communication for patients suffering from heart failure and could be most effective when the right timing, follow-up and involvement of important others was considered.

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.

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.

Low-dose ketamine in painful orthopaedic surgery: a systematic review and meta-analysis.

BACKGROUND: Ketamine is a phencyclidine intravenous anaesthetic that blocks N-methyl-d-aspartate receptors and HCN channels in the CNS. Lately it has gained acceptance in a low-dose form, with studies showing an analgesic benefit in orthopaedic surgery. Our goal was to critically appraise and synthesise current evidence regarding use of low-dose ketamine in major, painful orthopaedic surgeries. METHODS: We conducted searches in Medline, Embase, Cochrane, and specialty journals for randomised controlled trials (RCTs) that compared low-dose ketamine to placebo. Primary outcomes included total opioid use, time to first opioid, and VAS pain scores. Meta-analyses were undertaken in RevMan software using a random effects model. We rated the quality of the evidence using the GRADE Working Group criteria. RESULTS: We included 20 studies across four subgroups for meta-analysis. The overall quality of the evidence was moderate. Ketamine significantly decreased total opioid use and pain scores (VAS) at 24 and 48 h (Opioid: standardised mean difference [SMD] -0.82 [-1.24, -0.40], p=0.0001, and -0.65 [-1.03,-0.27], p=0.0008; VAS: SMD -0.53 [-0.91, -0.15], p=0.006 and -0.60 [-1.05, -0.16], p=0.008), and delayed the time to first opioid dose (SMD 0.64 [0.01, 1.27], p=0.05). Results for nausea and hallucinations were equivocal, whereas results for chronic pain were inconclusive. The most prominent effects were seen in total joint operations. CONCLUSION: Low-dose ketamine is an effective adjuvant that decreases pain and opioid requirements in painful orthopaedic procedures, especially in the first 24 h after procedure. Future research should focus on arthroscopic procedures and the incidence of chronic pain.

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.

Medications that reduce emergency hospital admissions: an overview of systematic reviews and prioritisation of treatments.

BACKGROUND: Rates of emergency hospitalisations are increasing in many countries, leading to disruption in the quality of care and increases in cost. Therefore, identifying strategies to reduce emergency admission rates is a key priority. There have been large-scale evidence reviews to address this issue; however, there have been no reviews of medication therapies, which have the potential to reduce the use of emergency health-care services. The objectives of this study were to review systematically the evidence to identify medications that affect emergency hospital admissions and prioritise therapies for quality measurement and improvement. METHODS: This was a systematic review of systematic reviews. We searched MEDLINE, PubMed, the Cochrane Database of Systematic Reviews & Database of Abstracts of Reviews of Effects, Google Scholar and the websites of ten major funding agencies and health charities, using broad search criteria. We included systematic reviews of randomised controlled trials that examined the effect of any medication on emergency hospital admissions among adults. We assessed the quality of reviews using AMSTAR. To prioritise therapies, we assessed the quality of trial evidence underpinning meta-analysed effect estimates and cross-referenced the evidence with clinical guidelines. RESULTS: We identified 140 systematic reviews, which included 1968 unique randomised controlled trials and 925,364 patients. Reviews contained 100 medications tested in 47 populations. We identified high-to moderate-quality evidence for 28 medications that reduced admissions. Of these medications, 11 were supported by clinical guidelines in the United States, the United Kingdom and Europe. These 11 therapies were for patients with heart failure (angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, aldosterone receptor antagonists and digoxin), stable coronary artery disease (intensive statin therapy), asthma exacerbations (early inhaled corticosteroids in the emergency department and anticholinergics), chronic obstructive pulmonary disease (long-acting muscarinic antagonists and long-acting beta-2 adrenoceptor agonists) and schizophrenia (second-generation antipsychotics and depot/maintenance antipsychotics). CONCLUSIONS: We identified 11 medications supported by strong evidence and clinical guidelines that could be considered in quality monitoring and improvement strategies to help reduce emergency hospital admission rates. The findings are relevant to health systems with a large burden of chronic disease and those managing increasing pressures on acute health-care services.

The effect of grapefruits (Citrus paradisi) on body weight and cardiovascular risk factors: A systematic review and meta-analysis of randomized clinical trials.

The aim of this systematic review was to evaluate the evidence for or against the effectiveness of grapefruits (Citrus paradisi) on body weight, blood pressure, and lipid profile. Electronic searches were conducted in MEDLINE, EMBASE, AMED, and the Cochrane Clinical Trials databases to identify relevant human randomized clinical trials (RCTs). Hand searches of bibliographies were also conducted. Only overweight and obese subjects were included. The reporting quality was assessed using the CONSORT checklist, and the strength of the overall body of evidence was rated based on the GRADE criteria. One hundred and fifty four citations were identified and three RCTs with a total of 250 participants were included. The RCTs were of moderate quality. A meta-analysis for change in body weight failed to reveal a significant difference between grapefruits and controls, MD: -0.45 kg (95% CI: -1.06 to 0.16; I2 = 53%, but analysis revealed a significant decrease in systolic blood pressure, MD: -2.43 mmHg (95% CI: -4.77 to -0.09; I2 = 0%). Paucity in the number of RCTs, short durations of interventions, and lack of an established minimum effective dose limit the conclusions that can be drawn about the effects of grapefruit on body weight and metabolic parameters. Further clinical trials evaluating the effects of grapefruit are warranted.

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.

Short-course versus long-course oral antibiotic treatment for infections treated in outpatient settings: a review of systematic reviews.

Purpose: To summarize the evidence comparing the effectiveness of short and long courses of oral antibiotics for infections treated in outpatient settings. Methods: We identified systematic reviews of randomized controlled trials for children and adults with bacterial infections treated in outpatient settings from Medline, Embase, CINAHL, Cochrane Database of Systematic Reviews and The Database of Review of Effects. Data were extracted on the primary outcome of clinical resolution and secondary outcomes. Results: We identified 30 potential reviews, and included 9. There was no difference in the clinical cure for children treated with short or long course antibiotics for Group A streptococcal tonsillopharyngitis (OR 1.03, 95% CI:0.97, 1.11); community acquired pneumonia (RR 0.99, 95% CI:0.97, 1.01); acute otitis media [<2 years old OR: 1.09 (95% CI:0.76, 1.57); ≥2 years old OR: 0.85 (95% CI:0.60, 1.21)]; or urinary tract infection (RR 1.06, 95% CI:0.64, 1.76). There was no difference in the clinical cure for adults treated with short or long course antibiotics for acute bacterial sinusitis (RR 0.95, 95% CI:0.81, 1.21); uncomplicated cystitis in non-pregnant women (RR 1.10, 95% CI:0.96, 1.25), or elderly women (RR: 0.98, 95% CI:0.62, 1.54); acute pyelonephritis (RR 1.03, 95% CI:0.80, 1.32); or community acquired pneumonia (RR: 0.96, 95% CI:0.74, 1.26). We found inadequate evidence about the effect on antibiotic resistance. Conclusions: This overview of systematic reviews has identified good quality evidence that short course antibiotics are as effective as longer courses for most common infections managed in ambulatory care. The impact on antibiotic resistance and associated treatment failure requires further study.

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.

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.

Pyruvate supplementation for weight loss: a systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Several slimming aids being sold as food supplements are widely available. One of them is pyruvate. Its efficacy in causing weight reduction in humans has not been fully established. The objective of this systematic review was to examine the efficacy of pyruvate in reducing body weight. METHODS: Electronic and nonelectronic searches were conducted to identify all relevant human randomized clinical trials. The bibliographies of all located articles were also searched. No restrictions in language or time were applied. Two independent reviewers extracted the data according to predefined criteria. A fixed-effect model was used to calculate mean differences (MD) and 95% confidence interval (CI). RESULTS: Nine trials were identified and 6 were included. All had methodological weaknesses. The meta-analysis revealed a statistically significant difference in body weight with pyruvate compared to placebo (MD: -0.72 kg; 95% CI: -1.24 to -0.20). The magnitude of the effect is small, and its clinical relevance is uncertain. Adverse events included gas, bloating, diarrhea, and increase in low-density lipoprotein (LDL) cholesterol. CONCLUSION: The evidence from randomized clinical trials does not convincingly show that pyruvate is efficacious in reducing body weight. Limited evidence exists about the safety of pyruvate. Future trials involving the use of this supplement should be more rigorous and better reported.