Comparative efficacy of single-inhaler triple therapies for COPD: A protocol for systematic review and network meta-analysis
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Introduction 2021 Global Initiative for Chronic Obstructive Lung Disease (GOLD) Reports recommends that patients with clinically significant symptoms and exacerbations of chronic obstructive pulmonary disease (COPD) should escalate to triple therapy, a combined use of inhaled corticosteroids (ICS), long-acting muscarinic antagonists (LAMA) and long-acting b2-agonists (LABA)(ICS/LAMA/LABA). Triple therapy in fixed-dose combinations (FDCs), i.e., combining ICS, LABA with LAMA and administrating by a single inhalation device, has appeared in recent years. This study aims to compare the efficacy of triple therapy in FDCs in treating patients with moderate to severe COPD. Methods and analyses Literature search will be conducted on PubMed, Embase and Web of science, according to pre-specified and corresponding search strategies, for relevant reports published since the inception dates of the databases. Randomised controlled trials (RCT) which compared the triple therapy in FDCs with other pharmacological therapies will be included. The Cochrane risk of bias assessment tool (RoB 2) will be used to assess the RCT quality. The outcomes will be analyzed as rate ratios and mean differences under a random-effects model in a frequentist network meta-analysis (NMA). Additional statistical analyses including subgroup analysis, sensitivity analysis, and publication bias analysis will be performed to assess the evidential heterogeneity and robustness. The strength of evidence from the NMA will be evaluated with the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) methods. Ethics and dissemination No ethics approval is required as this systematic review and network meta-analysis do not collect confidential personal data and do not carry out interventions in treating patients. Protocol registration number CRD42021240823 .Keywords:
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▼Glycopyrronium powder for inhalation (Seebri Breezhaler—Novartis) is a long-acting muscarinic receptor antagonist (LAMA), licensed as a maintenance bronchodilator treatment to relieve symptoms in adults with chronic obstructive pulmonary disease (COPD). 1 This is the third long-acting agent that has recently been licensed in the UK for use in people with COPD (see ▼Indacaterol for COPD 2 and ▼Aclidinium for COPD? 3 ). The company's promotional material claims that ‘Seebri is a once daily LAMA which supports cost effective prescribing at all stages of COPD’. 4 In this article we review the evidence for glycopyrronium and assess its place in the management of COPD.
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Objectives. Recent epidemiological studies suggest that metformin treatment may reduce the risks of cancer and overall cancer mortality among patients with diabetes mellitus (DM). However, data on hepatocellular carcinoma (HCC) are very limited and inconsistent. This meta-analysis was designed to pool data currently available to determine the association between metformin use and HCC among diabetic patients. Methods. The Medline and Embase databases were searched to identify the relevant studies between January 1966 and December 2011. The overall analysis was derived using a random-effects meta-analysis model (DerSimonian and Laird method). Subgroup analysis was performed to explore the source of heterogeneity and validate the results from overall analysis. The Newcastle-Ottawa Quality assessment scales were adopted for quality assessment; Begg's funnel plot and Egger's regression asymmetry test were used to detect the publication bias. Results. A total of seven studies were identified, including three cohort studies and four case-control studies. Based on the available data, the overall prevalence of HCC was 3.40% (562/16,549) in DM patients. The overall analysis showed a significantly reduced risk of HCC in metformin users versus nonusers in diabetic patients (relative risk (RR) 0.24, 95% confidence interval (CI) 0.13–0.46, p < 0.001). Fifteen subgroup analyses were performed, and most of them (12/15 = 80%) provided supporting evidence for the results of overall analysis. Begg's (Z = –0.15, p = 0.8819) and Egger's test (t = –0.79, p = 0.468) showed no significant risk of having a publication bias. Conclusion. Metformin treatment was associated with reduced risk of HCC in diabetic patients. To clarify this relationship, more high-quality studies are required.
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Are COPD patients taking triple combination inhalers being overmedicated during acute exacerbations?
Background: Triple combination inhalers containing inhaled corticosteroids (ICS), long-acting β2-adrenoceptor agonists (LABA) and long-acting muscarinic receptor antagonist (LAMA) can have beneficial effects in severe COPD not controlled on dual LABA/LAMA treatment. Their use has raised concern that patients admitted for acute COPD exacerbations may continue to receive them concurrently with nebulised short-acting muscarinic antagonist (SAMA). This has the potential to cause significant adverse effects. The extent to which this co-administration occurs in clinical practice has not been well studied to date. Methods: We assessed records of patients admitted to Oxford University Hospitals NHS in the last 6 months with primary diagnosis of acute COPD exacerbation, on a triple combination inhaler. Medication history on admission, inpatient medication chart and discharge summary were reviewed to determine treatments received and their timing. Results: 58/81(72%) were on triple combination single inhaler on admission and 23/81(28%) had one started during the admission. Co-administration of triple inhaler and SAMA was found in 40/81(49%). Triple inhaler was stopped whilst nebulised SAMA given in 24/81(30%) and 12/81(15%) had an ICS/LABA inhaler given instead. Only 6/81(8%) had the triple inhaler restarted later. Conclusion: Overmedication of LAMA and SAMA nebs at exacerbation is common. Whether SAMA is needed is unknown in patients on ICS/LABA/LAMA. Studies are needed to stop drug errors and improve outcomes.
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AIM:To assess systematically the association between regulatory T cells (Tregs) and hepatocellular carcinoma (HCC). METHODS:We searched Medline, Embase and Wanfang databases for literature on the populations of Tregs in HCC patients and controls, using the pooled OR and 95%CIs for assessment.There were no limitations with respect to publication date or language.The references of qualifying articles were also searched.We excluded studies with unclear data or overlapping studies.Twenty-three studies met our criteria, and the quality of these studies was assessed using the Scot-
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Runt-related transcription factor 3 (RUNX3) is a known regulator in the transforming growth factor (TGF)-β signaling pathway, which promoter methylation playing a crucial role in diverse neoplasias. However, the relationship between RUNX3 promoter methylation and non-small cell lung cancer (NSCLC) remains to be clarified.We searched Pubmed, Embase, Cochrane Central, and Chinese Biological Medicine database, for articles published in English or Chinese until March 7, 2014. Our main analyses were focused on the association between RUNX3 promoter methylation and risk of NSCLC by meta-analysis methods. If heterogeneity was observed, we used random effects model to calculate the overall odds ratios, otherwise fixed effects model was used. Subgroup analyses and meta-regression analyses were employed to detect the sources of the heterogeneity. Sensitivity analysis was performed to evaluate the stability of our studies. A funnel plot and Egger's test were conducted to investigate any potential publication bias.A total of 1,368 samples from 13 literatures were involved in this meta-analysis. The pooled odds ratio (OR) of RUNX3 methylation in NSCLC specimens compared to non-cancer controls was 6.70 [95% confidence interval (CI): 4.64-9.67]. In the analysis of specimen-types subgroup, the summary OR was 5.79 (95% CI: 3.97-8.46) for tissue specimen subgroup, and that was 45.64 (95% CI: 5.89-353.72) for serum specimen subgroup. The ORs for the age ≤60 years, 60-65 years and >65 years subgroup were 5.19 (95% CI: 3.27-8.24), 9.45 (95% CI: 2.45-36.45) and 13.23 (95% CI: 5.59-31.28) respectively. The result of meta-regression indicated that age was fundamental source of heterogeneity (coefficient =0.61, P=0.046, adjusted R(2) =100%). No publication bias was detected. In cancer specimens, the RUNX3 methylation was associated with histological type of the NSCLC, but no significant differences were found for RUNX3 methylation in relation to gender, smoking history, tumor TNM stage or tumor differentiation level.This meta-analysis of pooled data provides additional evidence to support a strong association between methylation of the RUNX3 promoter and NSCLC. RUNX3 methylation was increasing with age.
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Current COPD guidelines recommend 'triple therapy' with a long acting muscarinic antagonist and a combination of long acting β2-agonists/inhaled corticosteroid in patients with severe to very severe COPD or a history of frequent exacerbations if symptoms are not controlled with either inhaler alone. In the clinical field, withdrawal of either one inhaler in COPD patients receiving triple therapy (step down) often occurs. Our objective was to determine the outcome of step down in Korean Obstructive Lung Disease (KOLD) cohort with retrospectively reviewing the medical records. Triple group was defined patients treated with triple therapy over 2 years(n=109) and Step down group was defined patients treated with triple therapy at least for 1 year and followed over 1 year after withdrawal of either one inhaler(n=39). Index time (IT) was defined as the time point of withdrawal in Step down group or 1 year after the start of triple therapy in Triple group. Baseline demographic data, lung function, and patients reported outcomes at IT were not different between two groups, however, exacerbation frequency of the previous year was significantly lower in Step down group than Triple group (0.36±0.58 vs. 0.78±0.99, p=0.001). Even though, step down occurred in patients with lower exacerbation frequency, step down resulted in aggravating quality of life, decreasing exercise performance, and accelerating FEV1 decline, without increasing the frequency of exacerbation. Eleven patients (28%) in Step down group, re-started discontinued inhaler after 17±8 months. Withdrawing either one inhaler during treated with triple therapy in COPD patients should be done cautiously, which can aggravate patients' condition.
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Abstract There were conflictions and differences among the results of cross-sectional studies association between PM2.5 and COPD prevalence. We aimed to explore the real association between outdoor PM2.5 and COPD prevalence, analyze the possible cause to the differences and conflictions in previous cross-sectional studies. Cross-sectional literatures about the association between outdoor PM2.5 and COPD prevalence were selected up to 12 September 2018. Subgroup analysis was performed to explore the source of the heterogeneity. Publication bias was tested via funnel plot. Leave-one-out method was used to conduct influential analysis. Variance analysis was used to analyze the influence of concentration, literature quality and age (over 60 or not) on the ln (aOR) values. The initial search revealed 230 studies, of which 8 were selected. The heterogeneity in this study was significant (I2=62, P<0.01), and random effects model was used. The pooled OR for the association between PM2.5 and COPD prevalence is 2.32(95%CI, 1.91-2.82). There was no evidence of publication bias. Subgroup analysis showed the subgroup of age seemed to be the source of heterogeneity (P=0.0143, residual I2=0%). Variance analysis showed that the differences of ln (aOR) among each concentration group(p=0.0075) were statistically significant, the same as age groups(P=0.0234). This meta-analysis study demonstrated a conclusive association between PM2.5 and prevalence of COPD (OR: 2.32, 95%CI 1.91–2.82). The significant heterogeneity among selected studies was mainly caused by age (over 60 or not). High PM2.5 concentration should be needed in further research of the relationship between PM2.5 and chronic diseases.
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Background The evidence for association between Epstein-Barr virus (EBV) infection and risk of oral squamous cell carcinoma (OSCC) is inconsistent in the literature. Therefore, this meta-analysis was conducted to clarify this association. Methods A literature search was conducted in electronic databases for English- and Chinese-language publications until March 31, 2017 to include eligible case-control studies. The pooled odds ratio (OR) and 95% confidence interval (95% CI) were estimated to determine the association between EBV infection and OSCC risk using a fixed- or random-effects model based on heterogeneity. Publication bias was assessed using funnel plot analysis. Results A total of 13 case-control studies with 686 OSCC patients and 433 controls were included based on predetermined inclusion and exclusion criteria. The pooled OR with 95% CI between EBV infection and OSCC risk was 5.03 (1.80–14.01) with significant heterogeneity observed (I2 = 87%). The subgroup analysis indicates that the year of publication, study location, economic level, sample size, tissue type, detection method and marker, control type, and language might explain potential sources of heterogeneity. Publication bias was not observed, and sensitivity analysis showed stable results. Conclusions The results of the current meta-analysis suggest that EBV infection is statistically associated with increased risk of OSCC. However, additional high-quality studies with larger sample sizes are needed to further confirm the relationship between EBV and OSCC.
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To confirm whether eradication of H. pylori is associated with the occurrence of gastroesophageal reflux disease (GERD).We searched multiple medical databases for published randomized controlled trials (RCTs) from 2000 to 2012 comparing the incidence of GERD in adult patients receiving H. pylori treatment and those without treatment. The effects of H. pylori eradication were analyzed by calculating the pooled estimates for the number of new cases of GERD. Each racial subgroup of patients was analyzed using risk ratio (RR) by fixed effects models. The publication bias was assessed with funnel plot, Egger and Begg's test.Sixteen eligible RCTs were finally included in the analysis. Statistically analysis suggested H. pylori eradication was significantly correlated with the occurrence of GERD (RR 1.89, 95% CI 1.50-2.40). Funnel plot, Egger or Begg's test revealed no publication bias.H. pylori may have a positive effect on GERD especially in Asian patients and those with long-term follow-up, and eradication of H. pylori may cause GERD.
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