Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD

Objective We performed a review of studies of fluticasone propionate (FP)/salmeterol (SAL) (combination inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA)) in patients with COPD, which measured baseline (pretreatment) blood eosinophil levels, to test whether blood eosinophil levels ≥2% were associated with a greater reduction in exacerbation rates with ICS therapy. Methods Three studies of ≥1-year duration met the inclusion criteria. Moderate and severe exacerbation rates were analysed according to baseline blood eosinophil levels (<2% vs ≥2%). At baseline, 57–75% of patients had ≥2% blood eosinophils. Changes in FEV1 and St George’s Respiratory Questionnaire (SGRQ) scores were compared by eosinophil level. Results For patients with ≥2% eosinophils, FP/SAL was associated with significant reductions in exacerbation rates versus tiotropium (INSPIRE: n=719, rate ratio (RR)=0.75, 95% CI 0.60 to 0.92, p=0.006) and versus placebo (TRISTAN: n=1049, RR=0.63, 95% CI 0.50 to 0.79, p<0.001). No significant difference was seen in the <2% eosinophil subgroup in either study (INSPIRE: n=550, RR=1.18, 95% CI 0.92 to 1.51, p=0.186; TRISTAN: n=354, RR=0.99, 95% CI 0.67 to 1.47, p=0.957, respectively). In SCO30002 (n=373), no significant effects were observed (FP or FP/SAL vs placebo). No relationship was observed in any study between eosinophil subgroup and treatment effect on FEV1 and SGRQ. Discussion Baseline blood eosinophil levels may represent an informative marker for exacerbation reduction with ICS/LABA in patients with COPD and a history of moderate/severe exacerbations

Methionine and Related Compounds and Selenium Poisoning

The problem of selenium poisoning has been known for many years, but the mechanism by which this element exerts its toxicity has not been clarified. As a result, what control measures are now available are of an empirical nature, and they fail to the give the most desirable protection. In search of a better control mechanism, the role of compounds containing biologically active methyl groups has been studied. Some experimental work indicated that these types of compounds might indeed be involved in the metabolism of selenium. However, not all workers’ data were in agreement, and it was felt that further studies were needed

Ostracods from a Marmara Sea lagoon (Turkey) as tsunami indicators

This is the post print version of the article. The official published version can be obtained from the link below - Copyright @ Elsevier Ltd.A 352 cm long sediment core from Hersek Lagoon (Gulf of İzmit) was investigated for its ostracod species composition in order to evaluate the potential of ostracods to detect tsunami deposits in coastal environments. The Gulf of İzmit is the eastern bay of the Marmara Sea which is tectonically controlled by the North Anatolian Fault. Ostracod shells are rare in the lower third of the core, which probably represents a coastal wetland environment. According to radiocarbon dating of terrestrial plant remains, this unit was deposited between AD 500 and AD 800. Above, ostracod shells are abundant and dominantly monospecific, composed almost exclusively of the widespread brackish water ostracod Cyprideis torosa. This almost monospecific occurrence indicates the establishment and maintenance of the Hersek Lagoon after AD 800. Three distinct layers of mollusc shells and fragments contain ostracod shells of marine and to a lesser extent non-marine origin in addition to those of C. torosa. The shell layers are further characterized by significant maxima in total ostracod shell numbers. The high concentration of ostracod shells, the higher species numbers and the mixture of marine, lagoonal and non-marine ostracod shells shows that shell layers were formed as high-energy deposits resulting from tsunamis or large storms in the Marmara Sea. The partial occurrence of non-marine ostracod shells in the shell layers possibly indicates that tsunamis with extensive run-ups and significant backwash flows caused the high-energy deposits rather than large storms. The investigated sediments show that lagoonal ostracods can serve as good proxies for tsunamis or large storms through significant variations in total shell numbers, species numbers and the mixing of shells of different origin.Funding was provided by the European Union in the framework of the REL.I.E.F. (RELiable Information on Earthquake Faulting) project (EVG1-CT-2002-00069)

The Effect of ICS Withdrawal and Baseline Inhaled Treatment on Exacerbations in the IMPACT Study: A Randomized, Double-blind Multicenter Trial

RATIONALE: In the IMPACT trial fluticasone furoate/umeclidinium/ vilanterol (FF/UMEC/VI) significantly reduced exacerbations compared with FF/VI or UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease and a history of exacerbations. OBJECTIVES: Understand whether inhaled corticosteroid (ICS) withdrawal affected IMPACT results given direct transition from prior maintenance medication to study medication at randomization. METHODS: Exacerbations and change from baseline in trough forced expiratory volume in 1 second (FEV1) and St George's Respiratory Questionnaire (SGRQ) were analyzed by prior ICS use. Exacerbations were also analyzed excluding data from the first 30 days. MEASUREMENTS AND MAIN RESULTS: FF/UMEC/VI significantly reduced annual moderate/severe exacerbation rate versus UMEC/VI in prior ICS users (29% reduction; p<0.001), but only a numerical reduction was seen among prior ICS non-users (12% reduction; p=0.115). To minimize impact from ICS withdrawal, in an analysis excluding the first 30 days, FF/UMEC/VI continued to significantly reduce annual on-treatment moderate/severe exacerbation rate (19%; p<0.001) versus UMEC/VI. Benefit of FF/UMEC/VI versus UMEC/VI was seen for severe exacerbation rates, regardless of prior ICS use (prior ICS users: 35% reduction, p<0.001; non-ICS users: 35% reduction, p=0.018) and overall when excluding the first 30 days (29%, p<0.001). Improvements from baseline with FF/UMEC/VI versus UMEC/VI were also maintained throughout the study for both trough FEV1 and SGRQ regardless of prior ICS use. CONCLUSIONS: These data support important treatment effects from FF/UMEC/VI combination therapy on exacerbation reduction, lung function and quality of life that do not appear to be related to abrupt ICS withdrawal. FUNDING: GSK (CTT116855/NCT02164513). Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02164513. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

InforMing the PAthway of COPD Treatment (IMPACT) trial: fibrinogen levels predict risk of moderate or severe exacerbations

Background: Fibrinogen is the first qualified prognostic/predictive biomarker for exacerbations in patients with chronic obstructive pulmonary disease (COPD). The IMPACT trial investigated fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus FF/VI and UMEC/VI in patients with symptomatic COPD at risk of exacerbations. This analysis used IMPACT trial data to examine the relationship between fibrinogen levels and exacerbation outcomes in patients with COPD. Methods: 8094 patients with a fibrinogen assessment at Week 16 were included, baseline fibrinogen data were not measured. Post hoc analyses were performed by fibrinogen quartiles and by 3.5 g/L threshold. Endpoints included on-treatment exacerbations and adverse events of special interest (AESIs). Results: Rates of moderate, moderate/severe, and severe exacerbations were higher in the highest versus lowest fibrinogen quartile (0.75, 0.92 and 0.15 vs 0.67, 0.79 and 0.10, respectively). The rate ratios (95% confidence interval [CI]) for exacerbations in patients with fibrinogen levels ≥ 3.5 g/L versus those with fibrinogen levels < 3.5 g/L were 1.03 (0.95, 1.11) for moderate exacerbations, 1.08 (1.00, 1.15) for moderate/severe exacerbations, and 1.30 (1.10, 1.54) for severe exacerbations. There was an increased risk of moderate/severe exacerbation (hazard ratio [95% CI]: highest vs lowest quartile 1.16 [1.04, 1.228]; ≥ 3.5 g/L vs < 3.5 g/L: 1.09 [1.00, 1.16]) and severe exacerbation (1.35 [1.09, 1.69]; 1.27 [1.08, 1.47], respectively) with increasing fibrinogen level. Cardiovascular AESIs were highest in patients in the highest fibrinogen quartile. Conclusions: Rate and risk of exacerbations was higher in patients with higher fibrinogen levels. This supports the validity of fibrinogen as a predictive biomarker for COPD exacerbations, and highlights the potential use of fibrinogen as an enrichment strategy in trials examining exacerbation outcomes. Trial registration: NCT0216451

Prognostic value of clinically important deterioration in COPD: IMPACT trial analysis

Introduction: Clinically important deterioration (CID) is a multicomponent measure for assessing disease worsening in chronic obstructive pulmonary disease (COPD). This analysis investigated the prognostic value of a CID event on future clinical outcomes and the effect of single-inhaler triple versus dual therapy on reducing CID risk in patients in the IMPACT trial. Methods: IMPACT was a phase III, double-blind, 52-week, multicentre trial. Patients with symptomatic COPD and at least one moderate/severe exacerbation in the prior year were randomised 2:2:1 to fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg, FF/VI 100/25 µg or UMEC/VI 62.5/25 µg. CID at the time-point of interest was defined as a moderate/severe exacerbation, ≥100 mL decrease in trough forced expiratory volume in 1 s or deterioration in health status (increase of ≥4.0 units in St George's Respiratory Questionnaire total score or increase of ≥2.0 units in COPD Assessment Test score) from baseline. A treatment-independent post hoc prognostic analysis compared clinical outcomes up to week 52 in patients with/without a CID by week 28. A prospective analysis evaluated time to first CID with each treatment. Results: Patients with a CID by week 28 had significantly increased exacerbation rates after week 28, smaller improvements in lung function and health status at week 52 (all p<0.001), and increased risk of all-cause mortality after week 28 versus patients who were CID-free. FF/UMEC/VI significantly reduced CID risk versus dual therapies (all p<0.001). Conclusions: Prevention of short-term disease worsening was associated with better long-term clinical outcomes. FF/UMEC/VI reduced CID risk versus dual therapies; this effect may improve long-term prognosis in this population

InforMing the PAthway of COPD Treatment (IMPACT) Trial: Fibrinogen Levels Predict Risk of Moderate or Severe Exacerbations

Background: Fibrinogen is the frst qualifed prognostic/predictive biomarker for exacerbations in patients with chronic obstructive pulmonary disease (COPD). The IMPACT trial investigated futicasone furoate/umeclidinium/ vilanterol (FF/UMEC/VI) triple therapy versus FF/VI and UMEC/VI in patients with symptomatic COPD at risk of exacer‑ bations. This analysis used IMPACT trial data to examine the relationship between fbrinogen levels and exacerbation outcomes in patients with COPD. Methods: 8094 patients with a fbrinogen assessment at Week 16 were included, baseline fbrinogen data were not measured. Post hoc analyses were performed by fbrinogen quartiles and by 3.5 g/L threshold. Endpoints included on-treatment exacerbations and adverse events of special interest (AESIs). Results: Rates of moderate, moderate/severe, and severe exacerbations were higher in the highest versus lowest fibrinogen quartile (0.75, 0.92 and 0.15 vs 0.67, 0.79 and 0.10, respectively). The rate ratios (95% confidence interval [CI]) for exacerbations in patients with fibrinogen levels ≥ 3.5 g/L versus those with fibrinogen levels \u3c 3.5 g/L were 1.03 (0.95, 1.11) for moderate exacerbations, 1.08 (1.00, 1.15) for moderate/severe exacerbations, and 1.30 (1.10, 1.54) for severe exacerbations. There was an increased risk of moderate/severe exacerbation (hazard ratio [95% CI]: highest vs lowest quartile 1.16 [1.04, 1.228]; ≥ 3.5 g/L vs \u3c 3.5 g/L: 1.09 [1.00, 1.16]) and severe exacerbation (1.35 [1.09, 1.69]; 1.27 [1.08, 1.47], respectively) with increasing fibrinogen level. Cardiovascular AESIs were highest in patients in the highest fibrinogen quartile. Conclusions: Rate and risk of exacerbations was higher in patients with higher fbrinogen levels. This supports the validity of fbrinogen as a predictive biomarker for COPD exacerbations, and highlights the potential use of fbrinogen as an enrichment strategy in trials examining exacerbation outcomes

Reduction in All-Cause Mortality with Fluticasone Furoate/Umeclidinium/Vilanterol in COPD Patients

Rationale: The IMPACT trial demonstrated a significant reduction in all-cause mortality (ACM) risk with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI or UMEC/VI in patients with COPD at risk of future exacerbations. 574 patients were censored from the original analysis due to incomplete vital status information. Objective: Report ACM and impact of stepping down therapy, following collection of additional vital status data. Methods: Patients were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25µg, FF/VI 100/25µg or UMEC/VI 62.5/25µg following a run-in on their COPD therapies. Time to ACM was prespecified. Additional vital status data collection and subsequent analyses were performed post hoc. Measurements and Main Results: We report vital status data for 99.6% of the intention-to-treat population (n=10,355), documenting 98(2.36%) deaths on FF/UMEC/VI, 109(2.64%) on FF/VI, and 66(3.19%) on UMEC/VI. For FF/UMEC/VI, the hazard ratio for death was 0.72 (95%CI: 0.53,0.99;P=0.042) versus UMEC/VI and 0.89 (95%CI: 0.67,1.16;P=0.387) versus FF/VI. Independent adjudication confirmed lower rates of cardiovascular and respiratory death, and death associated with the patient’s COPD. Conclusions: In this secondary analysis of an efficacy outcome from the IMPACT trial, once-daily single-inhaler FF/UMEC/VI triple therapy reduced the risk of ACM versus UMEC/VI in patients with symptomatic COPD and a history of exacerbations. Funding: GSK(CTT116855/NCT02164513)

InforMing the PAthway of COPD Treatment (IMPACT Trial) Single-Inhaler Triple Therapy (Fluticasone Furoate/Umeclidinium/Vilanterol) Versus Fluticasone Furoate/Vilanterol and Umeclidinium/Vilanterol in Patients With COPD: Analysis o the Western Europe and North America Regions

Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by airflow limitation and progressive respiratory symptoms.1 Global public health trends estimate that the COPD burden will continue to rise, with COPD deaths estimated to increase to 4.4% of all deaths in Europe and 6.3% in the World Health Organization-defined region of the Americas by 2060.2 There are differences in the COPD burden in different regions reflecting variations in etiology,3,4 disease severity,5 symptoms,6 medication use,7 and health care systems and utilization.7 These differences may help inform therapeutic strategies to optimize therapeutic approaches to reducing symptoms and exacerbation risk.1 In the global InforMing the PAthway of COPD Treatment (IMPACT) trial, single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates and improved lung function and health-related quality of life versus FF/VI or UMEC/VI dual therapy in patients ≥40 years of age with symptomatic COPD and a history of exacerbations.8 Within trial populations, regional differences such as patient characteristics, treatment patterns, access to care and cultural/socioeconomic factors may dictate treatment choices and influence disease severity and progression in particular geographical locations. For example, a meta-analysis conducted in 2015 comprising 123 studies between 1990 and 2010 found that the overall prevalence of COPD as well as the rate of increase was higher in the Americas (including both North and South America) compared with Europe.9 Furthermore, a cross-sectional study assessing the burden of COPD symptoms in the United States and Europe found variations between patients across countries who had experienced at least 1 symptom of COPD.10 In Europe, patients with more frequent symptoms were more likely to experience worsening of symptoms and unexpected hospitalization. Whereas in the United States, patients with more frequent symptoms were not only more likely to experience worsening of symptoms but also longer lasting symptoms and a longer length of exacerbations.10 A further difference was that treatment adherence was higher in the United States than Europe, however, adherence was consistent across patients in Europe when assessed by modified Global initiative for chronic Obstructive Lung Disease (GOLD) 2014 groups11 but varied in the United States with adherence highest in the GOLD Group C and lowest in Group A.10 Therefore, it is important to evaluate how overall population results pertain to patients treated in particular regions. As IMPACT is one of the largest trials conducted in patients with COPD to date, we have the unique opportunity to analyze study outcomes in patients enrolled in Western Europe and North America, the 2 main regions from an enrollment perspective