Evidence Of Significant Clinical Benefit Research Articles

Evidence of clinical benefit of WHO essential anticancer medicines for children, 2011-2021.

Access to essential cancer medicines is a key determinant of childhood cancer survival. WHO published the Model List of Essential Medicine for Children (EMLc) and updated it every two years since 2007 to promote better access to medicines for children. This study aimed to assess whether the inclusion of essential anticancer medicines for respective indications for children was based on evidence of significant clinical benefit between 2011 and2021. We identified all anticancer medicine indications added to the WHO EMLc Section 8 since 2011 and extracted evidence of benefit documented in the corresponding technical reports. Evidence in children was defined as evidence that included participants under 12, and graded into five levels, according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. We analyzed whether each anticancer medicine indication was listed with documented OS benefit or improvements in surrogate measures based on the highest level of documented evidence in children. A total of 115 anticancer medicine indications were added to the EMLc from 2011 to 2021, of which 101 (87.8%) had some clinical evidence in children and 4 (3.5%) were added without any clinical evidence. Among the 101 medicine indications, none were added with level-1 evidence in children, and 43 (42.6%), 11 (10.9%), 41 (40.6%), and 6 (5.9%) were listed with level-2, level-3, level-4, and level-5 evidence in children, respectively. Only eight (7.9%) medicine indications were reported to have OS benefit, another 12 (11.9%) were reported to have improvements on surrogate measures, and 81 (80.2%) were listed in the EMLc without documented improvements in either OS or surrogate measures. Most anticancer medicine indications of the WHO EMLc were added based on limited evidence of statistically significant clinical benefit in children. Our results suggest that WHO should refine requirements for clinical benefit criteria and permissible forms, quality, and reporting of evidence of essential anticancer medicines for children, specify whether anticancer medicine indications have required evidence of clinical benefit in children, and provide further details in its technical reports that summarise the available evidence. Not applicable.

Reduction of social coverage for symptomatic slow-acting drugs for osteoarthritis: a disinvestment initiative in Argentina, 2015-2017

In April 2016, the National Institute of Social Services for Retirees and Pensioners discontinued its policy of 100% coverage for 159 drugs (the "social subsidy"), including symptomatic slow-acting drugs for osteoarthritis (SYSADOAs), due to insufficient evidence of significant clinical benefit. We evaluated the effect of this measure on the use of SYSADOAs as well as non-steroidal anti-inflammatory drugs (NSAIDs), which were unaffected by this policy change. We compared outpatient dispensations of SYSADOAs and NSAIDs from 2015 to 2017, measuring dispensed units, retail price, and out-of-pocket expenses for beneficiaries each month. After the change in coverage, there was a 61.6% total decrease in SYSADOA units dispensed, and a 63.4% decrease in the final sales price to the public, measured in constant values. Dispensation was not reoriented towards NSAIDs, which fell by 6.1%. The incidence of new treatments decreased (from 6.4 to 3.3 treatments per 1,000 beneficiaries per month), as did their continuity. Beneficiaries' out-of-pocket spending on SYSADOAs increased by 75.8% (at constant values). Disinvestment in interventions with questionable therapeutic value is an important tool in working toward the sustainability of health systems.

A randomised controlled trial of treatments of childhood anxiety disorder in the context of maternal anxiety disorder: clinical and cost-effectiveness outcomes.

BackgroundThis study evaluated whether clinical and economic outcomes from CBT for child anxiety disorders in the context of maternal anxiety disorders are improved by adding treatment focused on (a) maternal anxiety disorders or (b) mother–child interactions.MethodsTwo hundred and eleven children (7–12 years, 85% White British, 52% female) with a primary anxiety disorder, whose mothers also had a current anxiety disorder, were randomised to receive (a) child‐focused CBT with nonspecific control interventions (CCBT+Con), (b) CCBT with CBT for the maternal anxiety disorder (CCBT+MCBT), or (c) CCBT with an intervention targeting the mother–child interaction (CCBT+MCI). A cost‐utility analysis from a societal perspective was conducted using mother/child combined quality‐adjusted life years (QALYs). [Trial registration: https://doi.org/10.1186/isrctn19762288].Results MCBT was associated with immediate reductions in maternal anxiety compared to the nonspecific control; however, after children had also received CCBT, maternal outcomes in the CCBT+MCI and CCBT+Con arms improved and CCBT+MCBT was no longer superior. Neither CCBT+MCBT nor CCBT+MCI conferred a benefit over CCBT+Con in terms of child anxiety disorder diagnoses post‐treatment [primary outcome] (adj RR: 1.22 (95% CI: 0.88, 1.67), p = .23; adj RR: 1.21 (95% CI: 0.88, 1.65), p = .24, respectively) or global improvement ratings (adj RR: 1.25 (95% CI: 0.99, 1.57), p = .06; adj RR: 1.18 (95% CI: 0.93, 1.50), p = .17) or six and 12 months later. No significant differences between the groups were found on the main economic outcome measures (child/mother combined QALY mean difference: CCBT+MCBT vs. CCBT+Con: −0.04 (95% CI: −0.12, 0.04), p = .29; CCBT+MCI vs. CCBT+Con: 0.02 (95% CI: −0.05, −0.09), p = .54). CCBT+MCI was associated with nonsignificantly higher costs than CCBT (mean difference: £154 (95% CI: −£1,239, £1,547), p = .83) but, when taking into account sampling uncertainty, it may be cost‐effective compared with CCBT alone.ConclusionsGood outcomes were achieved for children and their mothers across treatment arms. There was no evidence of significant clinical benefit from supplementing CCBT with either CBT for the maternal anxiety disorder or treatment focussed on mother–child interactions, but the addition of MCI (and not MCBT) may be cost‐effective.

Importance of adherence and persistence in anticoagulant treatment: Advantages of once daily dosing

Despite evidence of significant clinical benefit, for patients with cardiovascular disease, adherence and persistence to treatment is often problematic. Once Daily dosing may increase treatment adherence and persistence. In this review, we discussed the effects of single dose anticoagulant use on treament adherence and persistence.

Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children.

Episodic viral wheeze (EVW) associated with viral respiratory tract infections is a common reason for pre-school children to utilise health care resources and for carers to take time away from employment. About a third of children experience a wheezing episode before the age of five years. EVW therefore represents a significant public health problem. Many pre-school children only wheeze in association with viral infections and in such cases EVW appears to be a separate entity from atopic asthma. Some trials have explored the effectiveness of leukotriene receptor antagonists (LTRAs) as regular (maintenance) or episodic (intermittent) treatment in this context. To evaluate the evidence for the efficacy and safety of maintenance and intermittent LTRAs in the management of EVW in children aged one to six years. We searched the Cochrane Airways Group register of trials with pre-specified terms. We performed additional searches by consulting the authors of identified trials, online trial registries of manufacturers' web sites, and reference lists of identified primary papers and reviews. Search results are current to June 2015. We included randomised controlled trials with a parallel-group or cross-over (for intermittent LTRA only) design. Maintenance was considered as treatment for more than two months and intermittent as less than 14 days. EVW was defined as a history of at least one previous episode of wheezing in association with a viral respiratory tract infection in the absence of symptoms between episodes. As far as possible, relevant specific data were obtained from authors of studies that included children of a wider age group or phenotype. Two authors independently assessed studies for inclusion in the review and assessed risk of bias. The primary outcome was number of children with one or more viral-induced episodes requiring one or more treatments with rescue oral corticosteroids. We analysed combined continuous data outcomes with the mean difference and dichotomous data outcomes with an odds ratio (OR). We identified five studies eligible for inclusion in the review (one investigated maintenance treatment, three intermittent therapy and one had both maintenance and intermittent treatment arms) these included 3741 participants. Each study involved oral montelukast and was of good methodological quality, but differed in choice of outcome measures thus limiting our ability to aggregate data across studies. Only primary outcome and adverse event data are reported in this abstract.For maintenance treatment, specific data obtained from a single study, pertaining to children with only an EVW phenotype, showed no statistically significant group reduction in the number of episodes requiring rescue oral corticosteroids associated with daily montelukast versus placebo (OR 1.20, 95% CI 0.70 to 2.06, moderate quality evidence).For intermittent LTRA, pooled data showed no statistically significant reduction in the number of episodes requiring rescue oral steroids in children treated with LTRA versus placebo (OR 0.77, 95% CI 0.48 to 1.25, moderate quality evidence). Specific data for children with an EVW phenotype obtained from a single study of intermittent montelukast treatment showed a small, but statistically significant reduction in unscheduled medical attendances due to wheeze (RR 0.83, 95% CI 0.71 to 0.98).For maintenance compared to intermittent LTRA treatment no data relating to the primary outcome of the review were identified.There were no other significant group differences identified in other secondary efficacy outcomes for maintenance or intermittent LTRA treatment versus placebo, or maintenance versus intermittent LTRA treatment. We collected descriptive data on adverse events as reported by four of the five included studies, and rates were similar between treatment and placebo groups.Potential heterogeneity in the phenotype of participants within and across trials is a limitation of the evidence. In pre-school children with EVW, there is no evidence of benefit associated with maintenance or intermittent LTRA treatment, compared to placebo, for reducing the number of children with one or more viral-induced episodes requiring rescue oral corticosteroids, and little evidence of significant clinical benefit for other secondary outcomes. Therefore until further data are available, LTRA should be used with caution in individual children. When used, we suggest a therapeutic trial is undertaken, during which efficacy should be carefully monitored. It is likely that children with an apparent EVW phenotype are not a homogeneous group and that subgroups may respond to LTRA treatment depending on the exact patho-physiological mechanisms involved.

Acute Renal Failure in Tetanus: Correspondence

To the Editor: We read the article ‘Acute renal failure in tetanus’ by Kaur et al. with interest [1]. The authors had reported acute kidney injury and myoglobinuria in a 10-y-old child with tetanus. We intend to highlight certain issues regarding the management of this child. The child was administered very high doses of intravenous diazepam (50 mg/kg/d) which could have predisposed to potentially life-threatening propylene glycol toxicity [2]. Propylene glycol (1, 2-propanediol) is a solvent used in intravenous preparation of lorazepam and diazepam. The toxic effects range from hyperosmolality, hemolysis, rhabdomyolysis, cardiac arrhythmia, seizure, and coma [3]. In addition, development of lactic acidosis, hypotension, and multisystem organ dysfunction in propylene glycol toxicity often mimic the features of septic shock. The normal range of serum creatinine in the 7–10 y age group is 0.22–0.6 mg/dL. The documented baseline serum creatinine level in this child was 0.9 mg/dL. This point to preexisting renal dysfunction at the onset; however, whether the underlying cause was ongoing rhabdomyolysis or autonomic dysfunction is a matter of debate. The child suffered sudden cardiac arrest on sixth day of hospitalization. The commonest cause of death in patients with severe tetanus on ventilator support is tetanusassociated autonomic dysfunction. Magnesium sulphate is useful for control of autonomic dysfunction in these patients. The muscle relaxation property of Magnesium sulphate controls spasms and cardiovascular manifestations (vasodilatation, lowering of heart rate, and reduction of systemic catecholamine release) and is responsible for ameliorating the ill effects of autonomic dysfunction. A recent randomized controlled trial also reiterated that magnesium sulphate infusion effected a reduction in the requirement of other drugs to control muscle spasms and cardiovascular instability without reducing the need for mechanical ventilation in patients with severe tetanus [4]. While managing acute kidney injury due to rhabdomyolysis, infusion of large volume of intravenous fluids within the first 24 h is associated with improved outcomes [5]. Alkalinization of the urine is also practiced routinely, but evidence of significant clinical benefit is lacking. A current consensus statement suggests that sodium bicarbonate administration is neither necessary nor superior to normal saline diuresis in increasing urine pH [5].

Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis.

Cystic fibrosis is an inherited condition resulting in thickened, sticky respiratory secretions. Respiratory failure, due to recurrent pulmonary infection and inflammation, is the most common cause of mortality. Muco-active therapies (e.g. dornase alfa and nebulized hypertonic saline) may decrease sputum viscosity, increase airway clearance of sputum, reduce infection and inflammation and improve lung function. Thiol derivatives, either oral or nebulized, have shown benefit in other respiratory diseases. Their mode of action is likely to differ according to the route of administration. There are several thiol derivatives, and it is unclear which of these may be beneficial in cystic fibrosis. To evaluate the efficacy and safety of nebulized and oral thiol derivatives in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, hand searches of relevant journals, abstract books and conference proceedings.Most recent search: 13 June 2013.We also conducted a PubMed search on 26 February 2013 for relevant published articles. Randomized and quasi-randomized controlled trials comparing nebulized or oral thiol derivatives to placebo or another thiol derivative in people with cystic fibrosis. The authors independently assessed trials for inclusion, analysed risk of bias and extracted data. Searches identified 23 trials; nine trials (255 participants) are included, of these seven trials are more than 10 years old. Three trials of nebulized thiol derivatives were identified (one compared 20% N-acetylcysteine to 2% N-acetylcysteine; another compared sodium-2-mercaptoethane sulphonate to 7% hypertonic saline; and another compared glutathione to 4% hypertonic saline). Although generally well-tolerated with no significant adverse effects, there was no evidence of significant clinical benefit in our primary outcomes in participants receiving these treatments.Six trials of oral thiol derivatives were identified. Three trials compared N-acetylcysteine to placebo; one compared N-acetylcysteine, ambroxol and placebo; one compared carbocysteine to ambroxol; and one compared low and high-dose N-acetylcysteine. Oral thiol derivatives were generally well-tolerated with no significant adverse effects, however there was no evidence of significant clinical benefit in our primary outcomes in participants receiving these treatments. We found no evidence to recommend the use of either nebulized or oral thiol derivatives in people with cystic fibrosis. There are very few good quality trials investigating the effect of these medications in cystic fibrosis, and further research is required to investigate the potential role of these medications in improving the outcomes of people with cystic fibrosis.

Renal angioplasty for treatment of hypertensive patients with fibromuscular dysplasia. No country for old men

Renal angioplasty for treatment of hypertensive patients with fibromuscular dysplasia. No country for old men

Postural changes to improve perfusion in acute hypovolaemia

Early management of hypoperfusion in the field has included the use of patient postures that are believed to increase venous return and to subsequently increase cardiac output, resulting in an improvement in perfusion. These postures are usually a Trendelenburg (head down position with the lower body elevated approximately 30 centimetres) or a raised leg posture with the torso horizontal. Despite apparent acceptance of these postures in the management of hypotension due to hypovolaemia there is conflicting advice in paramedic textbooks regarding the use of these postures, and as such this study sought to locate and evaluate evidence relating to the efficacy of these postures in the early management of hypoperfusion. The results of the review failed to find evidence of efficacy arising from the prehospital setting. Evidence from other health settings was subsequently reviewed to synthesise recommendations for paramedic practice. No evidence of significant clinical benefit was located, and the use of these postures by paramedics to improve perfusion should be reviewed on the basis of these findings.

Lack of efficacy of etanercept in Sjögren syndrome correlates with failed suppression of tumour necrosis factor α and systemic immune activation

Objective:To provide insight into the clinical failure of the tumour necrosis factor α (TNFα) inhibitor, etanercept, in primary Sjögren syndrome (pSS), an extensive analysis of the systemic immune profile of...