Comparative mortality risk of tiotropium administered via handihaler or respimat in COPD patients: are they equivalent?

BACKGROUND: Tiotropium bromide, once daily, long-acting anticholinergic bronchodilator is either administered by handihaler metered dose inhaler or by respimat soft mist inhaler. It has been proved to improve lung function, daily symptoms and quality of life and to decrease the exacerbation and hospitalisation rate of patients with Chronic Obstructive Pulmonary Disease (COPD). Although the efficacy of both formulations is undeniable, concerns have been raised on their effect on cardiovascular and general mortality. METHODS: Two independent authors systematically reviewed Medline, Scopus, Cochrane Library and ClinicalTrials.gov to collect clinical trials, observational studies and meta-analyses studying the safety of tiotropium. The reference list of all the included studies were also reviewed. RESULTS: Limited, early studies suggested a potential increase in cardiovascular and general mortality associated with tiotropium handihaler, but these data were outweighed by following larger trials, real-life studies and meta-analyses which proved the opposite. On the other hand, data on tiotropium respimat (5 µg) have been contradictory, with different studies suggesting increased cardiovascular and general mortality compared to handihaler (18 µg) or placebo, especially in patients with comorbid diseases. TIOSPIR trial suggests comparable safety of the two formulations. However the exclusion of patients with pre-existing unstable cardiovascular disease, moderate or severe kidney disease or any other significantly disease may limit the generizability of these results. CONCLUSION: Although the two tiotropium formulations have similar efficacy, current data cannot prove safety equivalence, since respimat may be associated with increased cardiovascular and general mortality, especially in patients with comorbid diseases.

Impact of long-term treatment with low-dose inhaled corticosteroids on the bone mineral density of chronic obstructive pulmonary disease patients: aggravating or beneficial?

BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is characterized by a low-level systemic chronic inflammatory activity that is responsible for many of the disease's extra-pulmonary manifestations, including osteoporosis and fragility fractures. These manifestations are also well-documented side-effects of oral corticosteroids. It was hypothesized that low levels of inhaled corticosteroids, due to their anti-inflammatory properties and their low circulating levels, might preserve the bone mineral density (BMD) of COPD patients. METHODS: Two hundred and fifty-one male ex-smokers with COPD patients grouped on the basis of their diffusion capacity value as predominantly bronchitic or predominantly emphysematic and 313 male controls with similar age and smoking history were enrolled in the study. Each of the patient's categories was randomized into two separate subgroups. Patients enrolled in subgroups B(neg) (n = 91, 36%) and E(neg) (n = 37, 14.7%) were treated with long-acting ß2-agonists and anticholinergics, while subgroups B(ICS) (n = 87, 35%) and E(ICS) (n = 38, 15.1%) were additionally receiving low-dose inhaled corticosteroids. Patients and controls were evaluated by clinical examination, lung function testing and BMD measurement every 6 months for 4 years. RESULTS: According to the findings, emphysematic patients demonstrated an increased rate of BMD loss compared with bronchitic patients (P = 0.01). Furthermore, a reduction of the annual BMD loss in bronchitic patients on inhaled corticosteroids (P = 0.02) was measured, without a corresponding benefit for the emphysematics (P = not significant). CONCLUSIONS: Long-term administration of low-dose inhaled corticosteroids decelerates the annual BMD loss in bronchitic patients, possibly by reducing both pulmonary and systemic chronic inflammation caused by COPD.

Management of asthma in childhood: study protocol of a systematic evidence update by the Paediatric Asthma in Real Life (PeARL) Think Tank.

INTRODUCTION: Clinical recommendations for childhood asthma are often based on data extrapolated from studies conducted in adults, despite significant differences in mechanisms and response to treatments. The Paediatric Asthma in Real Life (PeARL) Think Tank aspires to develop recommendations based on the best available evidence from studies in children. An overview of systematic reviews (SRs) on paediatric asthma maintenance management and an SR of treatments for acute asthma attacks in children, requiring an emergency presentation with/without hospital admission will be conducted. METHODS AND ANALYSIS: Standard methodology recommended by Cochrane will be followed. Maintenance pharmacotherapy of childhood asthma will be evaluated in an overview of SRs published after 2005 and including clinical trials or real-life studies. For evaluating pharmacotherapy of acute asthma attacks leading to an emergency presentation with/without hospital admission, we opted to conduct de novo synthesis in the absence of adequate up-to-date published SRs. For the SR of acute asthma pharmacotherapy, we will consider eligible SRs, clinical trials or real-life studies without time restrictions. Our evidence updates will be based on broad searches of Pubmed/Medline and the Cochrane Library. We will use A MeaSurement Tool to Assess systematic Reviews, V.2, Cochrane risk of bias 2 and REal Life EVidence AssessmeNt Tool to evaluate the methodological quality of SRs, controlled clinical trials and real-life studies, respectively.Next, we will further assess interventions for acute severe asthma attacks with positive clinical results in meta-analyses. We will include both controlled clinical trials and observational studies and will assess their quality using the previously mentioned tools. We will employ random effect models for conducting meta-analyses, and Grading of Recommendations Assessment, Development and Evaluation methodology to assess certainty in the body of evidence. ETHICS AND DISSEMINATION: Ethics approval is not required for SRs. Our findings will be published in peer reviewed journals and will inform clinical recommendations being developed by the PeARL Think Tank. PROSPERO REGISTRATION NUMBERS: CRD42020132990, CRD42020171624.

Prevalence and clinical implications of respiratory viruses in stable chronic obstructive pulmonary disease (COPD) and exacerbations: a systematic review and meta-analysis protocol.

INTRODUCTION: Both stable chronic obstructive pulmonary disease (COPD) and acute exacerbations represent leading causes of death, disability and healthcare expenditure. They are complex, heterogeneous and their mechanisms are poorly understood. The role of respiratory viruses has been studied extensively but is still not adequately addressed clinically. Through a rigorous evidence update, we aim to define the prevalence and clinical burden of the different respiratory viruses in stable COPD and exacerbations, and to investigate whether viral load of usual respiratory viruses could be used for diagnosis of exacerbations triggered by viruses, which are currently not diagnosed or treated aetiologically. METHODS AND ANALYSIS: Based on a prospectively registered protocol, we will systematically review the literature using standard methods recommended by the Cochrane Collaboration and the Grading of Recommendations Assessment, Development and Evaluation working group. We will search Medline/PubMed, Excerpta Medica dataBASE (EMBASE), the Cochrane Library, the WHO's Clinical Trials Registry and the proceedings of relevant international conferences on 2 March 2020. We will evaluate: (A) the prevalence of respiratory viruses in stable COPD and exacerbations, (B) differences in the viral loads of respiratory viruses in stable COPD vs exacerbations, to explore whether the viral load of prevalent respiratory viruses could be used as a diagnostic biomarker for exacerbations triggered by viruses and (C) the association between the presence of respiratory viruses and clinical outcomes in stable COPD and in exacerbations. ETHICS AND DISSEMINATION: Ethics approval is not required since no primary data will be collected. Our findings will be presented in national and international scientific conferences and will be published in peer reviewed journals. Respiratory viruses currently represent a lost opportunity to improve the outcomes of both stable COPD and exacerbations. Our work aspires to 'demystify' the prevalence and clinical burden of viruses in stable COPD and exacerbations and to promote clinical and translational research. PROSPERO REGISTRATION NUMBER: CRD42019147658.

Tiotropium HandiHaler improves the survival of patients with COPD: a systematic review and meta-analysis.

BACKGROUND: Tiotropium HandiHaler (TioH) has been shown to improve lung function, exacerbations, and quality of life when added to the pharmacotherapy of patients with stable chronic obstructive pulmonary disease (COPD). The purpose of this meta-analysis was to synthesize current evidence regarding the impact of TioH on the survival rate of these patients, which is still controversial. METHODS: A systematic search in the electronic databases of the Cochrane Library, Medline, Scopus, EMBASE, PschINFO, CINAHL, and Web of Science was conducted by two independent authors (December 2012). Randomized clinical trials (RCTs) comparing inhaled TioH versus control (placebo or open control) were included. Data on total mortality were extracted, and missing data were obtained from authors. Relative risk (RR) for total mortality was calculated for each study and pooled. Heterogeneity, the risk of bias, and the publication bias were assessed in accordance with Cochrane's guidance. RESULTS: Twenty-eight RCTs, evaluating 33,538 patients, met the inclusion criteria. Data were nonheterogeneous, so fixed-effects model analysis was used. The effect of TioH versus placebo was assessed in 19 RCTs, with a total population of 19,826 patients (31,914 patient years), of whom 1,018 died during the study period. A statistically significant decrease in all-cause mortality was associated with the administration of TioH [RR 0.86, 95% confidence interval (CI) 0.76-0.98]. The number needed to treat to prevent one fatality was estimated to be 64 (95% CI 56-110). Comparisons of tiotropium against six more comparators were identified, but the insufficient sample size did not allow robust comparisons with respect to mortality. CONCLUSION: Our meta-analysis of RCTs showed that TioH prolongs the survival of COPD patients compared with placebo. Further RCTs are needed to confirm the potential superiority of prescriptions with versus without TioH in mortality reduction.