| 1. |
- Edwards, Robert A., et al.
(author)
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Global phylogeography and ancient evolution of the widespread human gut virus crAssphage
- 2019
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In: Nature Microbiology. - : Springer Science and Business Media LLC. - 2058-5276. ; 4:10, s. 1727-1736
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Journal article (peer-reviewed)abstract
- Microbiomes are vast communities of microorganisms and viruses that populate all natural ecosystems. Viruses have been considered to be the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared with that of other environments. Here, we investigate the origin, evolution and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboration, we obtained DNA sequences of crAssphage from more than one-third of the world's countries and showed that the phylogeography of crAssphage is locally clustered within countries, cities and individuals. We also found fully colinear crAssphage-like genomes in both Old-World and New-World primates, suggesting that the association of crAssphage with primates may be millions of years old. Finally, by exploiting a large cohort of more than 1,000 individuals, we tested whether crAssphage is associated with bacterial taxonomic groups of the gut microbiome, diverse human health parameters and a wide range of dietary factors. We identified strong correlations with different clades of bacteria that are related to Bacteroidetes and weak associations with several diet categories, but no significant association with health or disease. We conclude that crAssphage is a benign cosmopolitan virus that may have coevolved with the human lineage and is an integral part of the normal human gut virome.
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| 2. |
- Lazaridis, Iosif, et al.
(author)
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Ancient human genomes suggest three ancestral populations for present-day Europeans
- 2014
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 513:7518, s. 409-
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Journal article (peer-reviewed)abstract
- We sequenced the genomes of a similar to 7,000-year-old farmer from Germany and eight similar to 8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes(1-4) with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians(3), who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations' deep relationships and show that early European farmers had similar to 44% ancestry from a 'basal Eurasian' population that split before the diversification of other non-African lineages.
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| 3. |
- Palkopoulou, Eleftheria, et al.
(author)
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A comprehensive genomic history of extinct and living elephants
- 2018
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In: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 115:11, s. E2566-E2574
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Journal article (peer-reviewed)abstract
- Elephantids are the world's most iconic megafaunal family, yet there is no comprehensive genomic assessment of their relationships. We report a total of 14 genomes, including 2 from the American mastodon, which is an extinct elephantid relative, and 12 spanning all three extant and three extinct elephantid species including an similar to 120,000-y-old straight-tusked elephant, a Columbian mammoth, and woolly mammoths. Earlier genetic studies modeled elephantid evolution via simple bifurcating trees, but here we show that interspecies hybridization has been a recurrent feature of elephantid evolution. We found that the genetic makeup of the straight-tusked elephant, previously placed as a sister group to African forest elephants based on lower coverage data, in fact comprises three major components. Most of the straight-tusked elephant's ancestry derives from a lineage related to the ancestor of African elephants while its remaining ancestry consists of a large contribution from a lineage related to forest elephants and another related to mammoths. Columbian and woolly mammoths also showed evidence of interbreeding, likely following a latitudinal cline across North America. While hybridization events have shaped elephantid history in profound ways, isolation also appears to have played an important role. Our data reveal nearly complete isolation between the ancestors of the African forest and savanna elephants for similar to 500,000 y, providing compelling justification for the conservation of forest and savanna elephants as separate species.
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| 4. |
- Zona, Donatella, et al.
(author)
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Earlier snowmelt may lead to late season declines in plant productivity and carbon sequestration in Arctic tundra ecosystems
- 2022
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Journal article (peer-reviewed)abstract
- Arctic warming is affecting snow cover and soil hydrology, with consequences for carbon sequestration in tundra ecosystems. The scarcity of observations in the Arctic has limited our understanding of the impact of covarying environmental drivers on the carbon balance of tundra ecosystems. In this study, we address some of these uncertainties through a novel record of 119 site-years of summer data from eddy covariance towers representing dominant tundra vegetation types located on continuous permafrost in the Arctic. Here we found that earlier snowmelt was associated with more tundra net CO2 sequestration and higher gross primary productivity (GPP) only in June and July, but with lower net carbon sequestration and lower GPP in August. Although higher evapotranspiration (ET) can result in soil drying with the progression of the summer, we did not find significantly lower soil moisture with earlier snowmelt, nor evidence that water stress affected GPP in the late growing season. Our results suggest that the expected increased CO2 sequestration arising from Arctic warming and the associated increase in growing season length may not materialize if tundra ecosystems are not able to continue sequestering CO2 later in the season.
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| 5. |
- He, Liyuan, et al.
(author)
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Global biogeography of fungal and bacterial biomass carbon in topsoil
- 2020
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In: Soil Biology and Biochemistry. - : Elsevier BV. - 0038-0717. ; 151
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Journal article (peer-reviewed)abstract
- Bacteria and fungi, representing two major soil microorganism groups, play an important role in global nutrient biogeochemistry. Biogeographic patterns of bacterial and fungal biomass are of fundamental importance for mechanistically understanding nutrient cycling. We synthesized 1323 data points of phospholipid fatty acid-derived fungal biomass C (FBC), bacterial biomass C (BBC), and fungi:bacteria (F:B) ratio in topsoil, spanning 11 major biomes. The FBC, BBC, and F:B ratio display clear biogeographic patterns along latitude and environmental gradients including mean annual temperature, mean annual precipitation, net primary productivity, root C density, soil temperature, soil moisture, and edaphic factors. At the biome level, tundra has the highest FBC and BBC densities at 3684 (95% confidence interval: 1678–8084) mg kg−1 and 428 (237–774) mg kg−1, respectively; desert has the lowest FBC and BBC densities at 16.92 (14.4–19.89) mg kg−1 and 6.83 (6.1–7.65) mg kg−1, respectively. The F:B ratio varies dramatically, ranging from 1.8 (1.6–2.1) in savanna to 8.6 (6.7–11.0) in tundra. An empirical model was developed for the F:B ratio and it is combined with a global dataset of soil microbial biomass C to produce global maps for FBC and BBC in 0–30 cm topsoil. Across the globe, the highest FBC is found in boreal forest and tundra while the highest BBC is in boreal forest and tropical/subtropical forest, the lowest FBC and BBC are in shrub and desert. Global stocks of living microbial biomass C were estimated to be 12.6 (6.6–16.4) Pg C for FBC and 4.3 (0.5–10.3) Pg C for BBC in topsoil. These findings advance our understanding of the global distribution of fungal and bacterial biomass, which facilitates the incorporation of fungi and bacteria into Earth system models. The global maps of bacterial and fungal biomass serve as a benchmark for validating microbial models in simulating the global C cycle under a changing climate.
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| 6. |
- Shukla, Soham, et al.
(author)
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Non-exacerbating patients with COPD from a UK perspective using the galaxy model
- 2021
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In: International Journal of COPD. - 1176-9106. ; 16, s. 3105-3118
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Journal article (peer-reviewed)abstract
- Introduction: Dual bronchodilators are recommended as maintenance treatment for patients with symptomatic COPD in the UK; further evidence is needed to evaluate cost-effectiveness versus monotherapy. Cost-effectiveness of umeclidinium/vilanterol versus umeclidinium and salmeterol from a UK healthcare perspective in patients without exacerbations in the previous year was assessed using post hoc EMAX trial data. Methods: The validated GALAXY model was populated with baseline characteristics and treatment effects from the non-exacerbating subgroup of the symptomatic EMAX population (COPD assessment test score ≥10) and 2020 UK healthcare and drug costs. Outputs included estimated exacerbation rates, costs, life-years (LYs), and quality-adjusted LYs (QALYs); incremental cost-effectiveness ratio (ICER) was calculated as incremental cost/QALY gained. The base case (probabilistic model) used a 10-year time horizon, assumed no treatment discontinuation, and discounted future costs and QALYs by 3.5% annually. Sensitivity and scenario analyses assessed robustness of model results. Results: Umeclidinium/vilanterol treatment was dominant versus umeclidinium and salmeterol, providing an additional 0.090 LYs (95% range: 0.035, 0.158) and 0.055 QALYs (−0.059, 0.168) with total cost savings of £690 (£231, £1306) versus umeclidinium, and 0.174 LYs (0.076, 0.286) and 0.204 QALYs (0.079, 0.326) with savings of £1336 (£1006, £2032) versus salmeterol. In scenario and sensitivity analyses, umeclidinium/vilanterol was dominant versus umeclidinium except over a 5-year time horizon (more QALYs at higher total cost; ICER=£4/QALY gained) and at the lowest estimate of the St George’s Respiratory Questionnaire treatment effect (fewer QALYs at lower total cost; ICER=£12,284/QALY gained); umeclidinium/vilanterol was consistently dominant versus salmeterol. At willingness-to-pay threshold of £20,000/QALY, probability that umeclidinium/vilanterol was cost-effective in this non-exacerbating subgroup was 95% versus umeclidinium and 100% versus salmeterol. Conclusion: Based on model predictions from a UK perspective, symptomatic patients with COPD and no exacerbations in the prior year receiving umeclidinium/vilanterol are expected to have better outcomes at lower costs versus umeclidinium and salmeterol.
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| 7. |
- Bjermer, Leif, et al.
(author)
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Dual bronchodilator therapy as first-line treatment in maintenance-naïve patients with symptomatic copd : A pre-specified analysis of the emax trial
- 2021
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In: International Journal of COPD. - 1176-9106. ; 16, s. 1939-1956
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Journal article (peer-reviewed)abstract
- Introduction: Limited prospective evidence is available to guide selection of first-line maintenance therapy in patients with COPD. This pre-specified analysis of the EMAX trial explored the efficacy and safety of dual-versus mono-bronchodilator therapy in maintenance-naïve and maintenance-treated patients. Methods: The 24-week EMAX trial evaluated lung function, symptoms (including rescue medication use), exacerbations, and safety with umeclidinium/vilanterol, umeclidinium, and salmeterol in symptomatic patients at low exacerbation risk who were not receiving inhaled corticosteroids. Maintenance-naïve and maintenance-treated subgroups were defined by maintenance bronchodilator use 30 days before screening. Results: The analysis included 749 (31%) maintenance-naïve and 1676 (69%) maintenance-treated patients. For both subgroups, improvements from baseline in trough FEV1 at Week 24 (primary endpoint) were greater with umeclidinium/vilanterol versus umeclidinium (mean difference [95% CI]; maintenance-naïve: 44 mL [1, 87]; maintenance-treated: 77 mL [50, 104]), and salmeterol (maintenance-naïve: 128 mL [85, 171]; maintenance-treated: 145 mL [118, 172]), and in rescue medication inhalations/day over 24 weeks versus umeclidinium (maintenance-naïve: −0.44 [−0.73, −0.16]; maintenance-treated: −0.28 [−0.45, −0.12]) and salmeterol (maintenance-naïve: −0.37 [−0.66, −0.09]; maintenance-treated: −0.25 [−0.41, −0.08]). In maintenance-naïve patients, umeclidinium/vilanterol numerically improved scores at Week 24 for Transition Dyspnea Index versus umeclidinium (0.37 [−0.21, 0.96]) and versus salmeterol (0.47 [−0.10, 1.05]) and Evaluating Respiratory Symptoms–COPD versus umeclidinium (−0.26 [−1.04, 0.53]) and versus salmeterol (−0.58 [−1.36, 0.20]), with similar improvements seen in maintenance-treated patients. All treatments were well tolerated across both subgroups. Conclusion: Similar to maintenance-treated patients, maintenance-naïve patients receiving umeclidinium/vilanterol showed greater improvements in lung function and symptoms com-pared with patients receiving umeclidinium or salmeterol. These findings provide support for the consideration of dual bronchodilator treatment in symptomatic maintenance-naïve patients with COPD.
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| 8. |
- Bjermer, Leif H., et al.
(author)
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Efficacy and Safety of Umeclidinium/Vilanterol in Current and Former Smokers with COPD : A Prespecified Analysis of The EMAX Trial
- 2021
-
In: Advances in Therapy. - : Springer Science and Business Media LLC. - 0741-238X .- 1865-8652. ; 38:9, s. 4815-4835
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Journal article (peer-reviewed)abstract
- Introduction: Smoking may reduce the efficacy of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD), but its impact on bronchodilator efficacy is unclear. This analysis of the EMAX trial explored efficacy and safety of dual- versus mono-bronchodilator therapy in current or former smokers with COPD. Methods: The 24-week EMAX trial evaluated lung function, symptoms, health status, exacerbations, clinically important deterioration, and safety with umeclidinium/vilanterol, umeclidinium, and salmeterol in symptomatic patients at low exacerbation risk who were not receiving ICS. Current and former smoker subgroups were defined by smoking status at screening. Results: The analysis included 1203 (50%) current smokers and 1221 (50%) former smokers. Both subgroups demonstrated greater improvements from baseline in trough FEV1 at week 24 (primary endpoint) with umeclidinium/vilanterol versus umeclidinium (least squares [LS] mean difference, mL [95% CI]; current: 84 [50, 117]; former: 49 [18, 80]) and salmeterol (current: 165 [132, 198]; former: 117 [86, 148]) and larger reductions in rescue medication inhalations/day over 24 weeks versus umeclidinium (LS mean difference [95% CI]; current: − 0.42 [− 0.63, − 0.20]; former: − 0.25 − 0.44, − 0.05]) and salmeterol (current: − 0.28 [− 0.49, − 0.06]; former: − 0.29 [− 0.49, − 0.09]). Umeclidinium/vilanterol increased the odds (odds ratio [95% CI]) of clinically significant improvement at week 24 in Transition Dyspnea Index versus umeclidinium (current: 1.54 [1.16, 2.06]; former: 1.32 [0.99, 1.75]) and salmeterol (current: 1.37 (1.03, 1.82]; former: 1.60 [1.20, 2.13]) and Evaluating Respiratory Symptoms–COPD versus umeclidinium (current: 1.54 [1.13, 2.09]; former: 1.50 [1.11, 2.04]) and salmeterol (current: 1.53 [1.13, 2.08]; former: 1.53 [1.12, 2.08]). All treatments were well tolerated in both subgroups. Conclusions: In current and former smokers, umeclidinium/vilanterol provided greater improvements in lung function and symptoms versus umeclidinium and salmeterol, supporting consideration of dual-bronchodilator therapy in symptomatic patients with COPD regardless of their smoking status.
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| 9. |
- He, Liyuan, et al.
(author)
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Dynamics of Fungal and Bacterial Biomass Carbon in Natural Ecosystems: Site-level Applications of the CLM-Microbe Model
- 2021
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In: Journal of Advances in Modeling Earth Systems. - 1942-2466. ; 13:2
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Journal article (peer-reviewed)abstract
- Explicitly representing microbial processes has been recognized as a key improvement to Earth system models for the realistic projections of soil carbon (C) and climate dynamics. The CLM‐Microbe model builds upon the CLM4.5 and explicitly represents two major soil microbial groups, fungi and bacteria. Based on the compiled time‐series data of fungal (FBC) and bacterial (BBC) biomass C from nine biomes, we parameterized and validated the CLM‐Microbe model, and further conducted sensitivity analysis and uncertainty analysis for simulating C cycling. The model performance was evaluated with mean absolute error (MAE), root mean square error (RMSE), and coefficient of determination (R2) for relative change in FBC and BBC. The CLM‐Microbe model is able to reasonably capture the seasonal dynamics of FBC and BBC across biomes, particularly for tropical/subtropical forest, temperate broadleaf forest, and grassland, with MAE < 0.49 for FBC and <0.36 for BBC and RMSE <0.52 FBC and <0.39 for BBC, while R2 values are relatively smaller in some biomes (e.g., shrub) due to small sample sizes. We found good consistencies between simulated and observed FBC (R2=0.70, P<0.001) and BBC (R2=0.26, P<0.05) on average across biomes, but the model is not able to fully capture the large variation in observed FBC and BBC. Sensitivity analysis shows the most critical parameters are turnover rate, carbon‐to‐nitrogen ratio of fungi and bacteria, and microbial assimilation efficiency. This study confirms that the explicit representation of soil microbial mechanisms enhances model performance in simulating C variables such as heterotrophic respiration and soil organic C density. The further application of the CLM‐Microbe model would deepen our understanding of microbial contributions to the global C cycle.
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| 10. |
- Kerwin, Edward M., et al.
(author)
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Early and sustained symptom improvement with umeclidinium/vilanterol versus monotherapy in COPD : a post hoc analysis of the EMAX randomised controlled trial
- 2020
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In: Therapeutic Advances in Respiratory Disease. - : SAGE Publications. - 1753-4658 .- 1753-4666. ; 14
-
Journal article (peer-reviewed)abstract
- Background: In chronic obstructive pulmonary disease (COPD), both the time needed for patients to gain symptom improvement with long-acting bronchodilator therapy and whether an early response is predictive of a sustained response is unknown. This study aimed to investigate how quickly meaningful symptom responses are seen in patients with COPD with bronchodilator therapy and whether these responses are sustained. Methods: Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a 24-week, double-blind, double-dummy, parallel-group trial that randomised patients to umeclidinium/vilanterol (UMEC/VI), umeclidinium or salmeterol. Daily Evaluating Respiratory Symptoms in COPD (E-RS:COPD) score and rescue salbutamol use were captured via an electronic diary and analysed initially in 4-weekly periods. Post hoc analyses assessed change from baseline in daily E-RS:COPD score and rescue medication use weekly (Weeks 1–8), and association between E-RS:COPD responder status at Weeks 1–4 and later time points. Results: In the intent-to-treat population (n = 2425), reductions from baseline in E-RS:COPD scores and rescue medication use were apparent from Day 2 with all treatments. Treatment differences for UMEC/VI versus either monotherapy plateaued by Week 4–8 and were sustained at Weeks 21–24; improvements were consistently greater with UMEC/VI. For all treatments, most patients (60–85%) retained their Weeks 1–4 E-RS:COPD responder/non-responder status at Weeks 21−24. Among patients receiving UMEC/VI who were E-RS:COPD responders at Weeks 1–4, 70% were responders at Weeks 21–24. Conclusion: Patients with symptomatic COPD had greater potential for early symptom improvements with UMEC/VI versus either monotherapy. This benefit was generally maintained for 24 weeks. Early monitoring of treatment response can provide clinicians with an early indication of a patient’s likely longer-term response to prescribed bronchodilator treatment and will facilitate appropriate early adjustments in care. Clinical Trial Registration: NCT03034915, 2016-002513-22 (EudraCT Number). The reviews of this paper are available via the supplemental material section.
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| 11. |
- Kerwin, Edward M., et al.
(author)
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How can the findings of the EMAX trial on long-acting bronchodilation in chronic obstructive pulmonary disease be applied in the primary care setting?
- 2023
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In: Chronic Respiratory Disease. - 1479-9723. ; 20
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Research review (peer-reviewed)abstract
- This review addresses outstanding questions regarding initial pharmacological management of chronic obstructive pulmonary disease (COPD). Optimizing initial treatment improves clinical outcomes in symptomatic patients, including those with low exacerbation risk. Long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) dual therapy improves lung function versus LAMA or LABA monotherapy, although other treatment benefits have been less consistently observed. The benefits of dual bronchodilation in symptomatic patients with COPD at low exacerbation risk, and its duration of efficacy and cost effectiveness in this population, are not yet fully established. Questions remain on the impact of baseline symptom severity, prior treatment, degree of reversibility to bronchodilators, and smoking status on responses to dual bronchodilator treatment. Using evidence from EMAX (NCT03034915), a 6-month trial comparing the LAMA/LABA combination umeclidinium/vilanterol with umeclidinium and salmeterol monotherapy in symptomatic patients with COPD at low exacerbation risk who were inhaled corticosteroid-naïve, we describe how these findings can be applied in primary care.
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| 12. |
- Maltais, François, et al.
(author)
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Applying key learnings from the EMAX trial to clinical practice and future trial design in COPD
- 2022
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In: Respiratory Medicine. - : Elsevier BV. - 0954-6111. ; 200
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Research review (peer-reviewed)abstract
- Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a large, multicentre, multi-national, randomised, double-blind, 24-week trial. EMAX evaluated the efficacy and safety of dual bronchodilator therapy with umeclidinium bromide (UMEC)/vilanterol (VI) versus monotherapy with either UMEC or salmeterol (SAL) in symptomatic patients with chronic obstructive pulmonary disease (COPD) at low exacerbation risk who were not taking concomitant inhaled corticosteroid (ICS). EMAX generated evidence covering a wide range of patient-centred endpoints in COPD in addition to measures of lung function, clinical deterioration and safety. In addition, prospective and post hoc secondary analyses have generated clinically valuable information regarding the effects of baseline patient characteristics on treatment outcomes. Importantly, as concomitant ICS use was not permitted in this study, EMAX compared dual long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) therapy with LAMA or LABA monotherapy without potential confounding due to concurrent ICS use or withdrawal. EMAX demonstrated beneficial treatment effects of UMEC/VI over UMEC or SAL monotherapy as maintenance treatment across a range of different patient characteristics, with no forfeit in safety. Thus, the trial provided novel insights into the role of LAMA/LABA versus LABA and LAMA monotherapies as maintenance therapy for patients with symptomatic COPD at low risk of exacerbations. This article will explore the clinical implications of the main findings to date of the EMAX trial and consider the key learnings this trial offers for future trial design in COPD.
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| 13. |
- Rainsley, Eleanor, et al.
(author)
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Pleistocene glacial history of the New Zealand subantarctic islands
- 2019
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In: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 15:2, s. 423-448
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Journal article (peer-reviewed)abstract
- The New Zealand subantarctic islands of Auckland and Campbell, situated between the subtropical front and the Antarctic Convergence in the Pacific sector of the Southern Ocean, provide valuable terrestrial records from a globally important climatic region. Whilst the islands show clear evidence of past glaciation, the timing and mechanisms behind Pleistocene environmental and climate changes remain uncertain. Here we present a multidisciplinary study of the islands-including marine and terrestrial geomorphological surveys, extensive analyses of sedimentary sequences, a comprehensive dating programme, and glacier flow line modelling-to investigate multiple phases of glaciation across the islands. We find evidence that the Auckland Islands hosted a small ice cap 384 000 +/- 26 000 years ago (384 +/- 26 ka), most likely during Marine Isotope Stage 10, a period when the subtropical front was reportedly north of its present-day latitude by several degrees, and consistent with hemispheric-wide glacial expansion. Flow line modelling constrained by field evidence suggests a more restricted glacial period prior to the LGM that formed substantial valley glaciers on the Campbell and Auckland Islands around 72-62 ka. Despite previous interpretations that suggest the maximum glacial extent occurred in the form of valley glaciation at the Last Glacial Maximum (LGM; similar to 21 ka), our combined approach suggests minimal LGM glaciation across the New Zealand subantarctic islands and that no glaciers were present during the Antarctic Cold Reversal (ACR; similar to 15-13 ka). Instead, modelling implies that despite a regional mean annual air temperature depression of similar to 5 degrees C during the LGM, a combination of high seasonality and low precipitation left the islands incapable of sustaining significant glaciation. We suggest that northwards expansion of winter sea ice during the LGM and subsequent ACR led to precipitation starvation across the middle to high latitudes of the Southern Ocean, resulting in restricted glaciation of the subantarctic islands.
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| 14. |
- Vogelmeier, Claus F., et al.
(author)
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Efficacy of umeclidinium/vilanterol according to the degree of reversibility of airflow limitation at screening : a post hoc analysis of the EMAX trial
- 2021
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In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 22:1
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Journal article (peer-reviewed)abstract
- Background: In patients with chronic obstructive pulmonary disease (COPD), the relationship between short-term bronchodilator reversibility and longer-term response to bronchodilators is unclear. Here, we investigated whether the efficacy of long-acting bronchodilators is associated with reversibility of airflow limitation in patients with COPD with a low exacerbation risk not receiving inhaled corticosteroids. Methods: The double-blind, double-dummy EMAX trial randomised patients to umeclidinium/vilanterol 62.5/25 µg once daily, umeclidinium 62.5 µg once daily, or salmeterol 50 µg twice daily. Bronchodilator reversibility to salbutamol was measured once at screening and defined as an increase in forced expiratory volume in 1 s (FEV1) of ≥ 12% and ≥ 200 mL 10−30 min post salbutamol. Post hoc, fractional polynomial (FP) modelling was conducted using the degree of reversibility (mL) at screening as a continuous variable to investigate its relationship to mean change from baseline in trough FEV1 and self-administered computerised-Transition Dyspnoea Index (SAC-TDI) at Week 24, Evaluating Respiratory Symptoms-COPD (E-RS) at Weeks 21–24, and rescue medication use (puffs/day) over Weeks 1–24. Analyses were conducted across the full range of reversibility (−850–896 mL); however, results are presented for the range −100–400 mL because there were few participants with values outside this range. Results: The mean (standard deviation) reversibility was 130 mL (156) and the median was 113 mL; 625/2425 (26%) patients were reversible. There was a trend towards greater improvements in trough FEV1, SAC-TDI, E-RS and rescue medication use with umeclidinium/vilanterol with higher reversibility. Improvements in trough FEV1 and reductions in rescue medication use were greater with umeclidinium/vilanterol compared with either monotherapy across the range of reversibility. Greater improvements in SAC-TDI and E-RS total scores were observed with umeclidinium/vilanterol versus monotherapy in the middle of the reversibility range. Conclusions: FP analyses suggest that patients with higher levels of reversibility have greater improvements in lung function and symptoms in response to bronchodilators. Improvements in lung function and rescue medication use were greater with umeclidinium/vilanterol versus monotherapy across the full range of reversibility, suggesting that the dual bronchodilator umeclidinium/vilanterol may be an appropriate treatment for patients with symptomatic COPD, regardless of their level of reversibility.
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| 15. |
- Vogelmeier, Claus F., et al.
(author)
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Impact of baseline COPD symptom severity on the benefit from dual versus mono-bronchodilators : an analysis of the EMAX randomised controlled trial
- 2020
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In: Therapeutic Advances in Respiratory Disease. - : SAGE Publications. - 1753-4658 .- 1753-4666. ; 14
-
Journal article (peer-reviewed)abstract
- Rationale: Symptom relief is a key treatment goal in patients with chronic obstructive pulmonary disease (COPD). However, there are limited data available on the response to bronchodilator therapy in patients at low risk of exacerbations with different levels of symptom severity. This study compared treatment responses in patients with a range of symptom severities as indicated by baseline COPD assessment test (CAT) scores. Methods: The 24-week EMAX trial evaluated the benefits of umeclidinium/vilanterol versus umeclidinium or salmeterol in symptomatic patients at low exacerbation risk who were not receiving inhaled corticosteroids. This analysis assessed lung function, symptoms, health status, and short-term deterioration outcomes in subgroups defined by a baseline CAT score [<20 (post hoc) and ⩾20 (pre-specified)]. Outcomes were also assessed using post hoc fractional polynomial modelling with continuous transformations of baseline CAT score covariates. Results: Of the intent-to-treat population (n = 2425), 56% and 44% had baseline CAT scores of <20 and ⩾20, respectively. Umeclidinium/vilanterol demonstrated favourable improvements compared with umeclidinium and salmeterol for the majority of outcomes irrespective of the baseline CAT score, with the greatest improvements generally observed in patients with CAT scores <20. Fractional polynomial analyses revealed consistent improvements in lung function, symptoms and reduction in rescue medication use with umeclidinium/vilanterol versus umeclidinium and salmeterol across a range of CAT scores, with the largest benefits seen in patients with CAT scores of approximately 10–21. Conclusions: Patients with symptomatic COPD benefit similarly from dual bronchodilator treatment with umeclidinium/vilanterol. Fractional polynomial analyses demonstrated the greatest treatment differences favouring dual therapy in patients with a CAT score <20, although benefits were seen up to scores of 30. This suggests that dual bronchodilation may be considered as initial therapy for patients across a broad range of symptom severities, not only those with severe symptoms (CAT ⩾20). Trial registration: NCT03034915, 2016-002513-22 (EudraCT number). The reviews of this paper are available via the supplemental material section.
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| 16. |
- Vogelmeier, Claus F., et al.
(author)
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Wtreatment of copd with long-acting bronchodilators : Association between early and longer-term clinically important improvement
- 2021
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In: International Journal of COPD. - 1176-9106. ; 16, s. 1215-1226
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Journal article (peer-reviewed)abstract
- Introduction: This post hoc analysis of the “Early MAXimization of bronchodilation for improving COPD stability” (EMAX) trial investigated whether patients achieving early clinically important improvement (CII) sustained longer-term improvements and lower risk of clinically important deterioration (CID). Methods: Patients were randomized to umeclidinium/vilanterol, umeclidinium, or salmeterol for 24 weeks. The patient-reported outcomes (PROs) Transition Dyspnea Index (TDI), Evaluating Respiratory Symptoms, St George’s Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT) were assessed. CII, defined as attaining minimum clinically important differences (MCID) in ≥2 PROs, was assessed at Weeks 4, 12 and 24. CID was defined as a deterioration in CAT, SGRQ, TDI by the MCID and/or a moderate/severe exacerbation from Day 30. Results: Of 2425 patients, 50%, 53% and 51% achieved a CII at Weeks 4, 12 and 24, respectively. Patients with a CII at Week 4 versus those without had significantly greater odds of achieving a CII at Weeks 12 and 24 (odds ratio: 5.57 [95% CI: 4.66, 6.66]; 4.09 [95% CI: 3.44, 4.86]). The risk of a CID was higher in patients who did not achieve a CII at Week 4 compared with patients who did (hazard ratio [95% CI]: 2.09 [1.86, 2.34]). Patients treated with umeclidinium/vilanterol versus either monotherapy had significantly greater odds of achieving CII at Weeks 4, 12 and 24. Conclusion: Achieving a CII at Week 4 was associated with longer-term improvement in PROs and a reduced risk of deterioration. Further research is required to investigate the importance of an early response to treatment on the long-term disease course.
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