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BackgroundProspective evidence is lacking regarding incremental benefits of long-acting dual- versus mono-bronchodilation in improving symptoms and preventing short-term disease worsening/treatment failure in low exacerbation risk patients with chronic obstructive pulmonary disease (COPD) not receiving inhaled corticosteroids.MethodsThe 24-week, double-blind, double-dummy, parallel-group Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised patients at low exacerbation risk not receiving inhaled corticosteroids, to umeclidinium/vilanterol 62.5/25 μg once-daily, umeclidinium 62.5 μg once-daily or salmeterol 50 μg twice-daily. The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at Week 24. The study was also powered for the secondary endpoint of Transition Dyspnoea Index at Week 24. Other efficacy assessments included spirometry, symptoms, heath status and short-term disease worsening measured by the composite endpoint of clinically important deterioration using three definitions.ResultsChange from baseline in trough FEV1 at Week 24 was 66 mL (95% confidence interval [CI]: 43, 89) and 141 mL (95% CI: 118, 164) greater with umeclidinium/vilanterol versus umeclidinium and salmeterol, respectively (both p < 0.001). Umeclidinium/vilanterol demonstrated consistent improvements in Transition Dyspnoea Index versus both monotherapies at Week 24 (vs umeclidinium: 0.37 [95% CI: 0.06, 0.68], p = 0.018; vs salmeterol: 0.45 [95% CI: 0.15, 0.76], p = 0.004) and all other symptom measures at all time points. Regardless of the clinically important deterioration definition considered, umeclidinium/vilanterol significantly reduced the risk of a first clinically important deterioration compared with umeclidinium (by 16–25% [p < 0.01]) and salmeterol (by 26–41% [p < 0.001]). Safety profiles were similar between treatments.ConclusionsUmeclidinium/vilanterol consistently provides early and sustained improvements in lung function and symptoms and reduces the risk of deterioration/treatment failure versus umeclidinium or salmeterol in symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids. These findings suggest a potential for early use of dual bronchodilators to help optimise therapy in this patient group.

IntroductionReal-world trial data comparing single- with multiple-inhaler triple therapy (MITT) in COPD patients are currently lacking. The effectiveness of once-daily single-inhaler fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) and MITT were compared in usual clinical care.MethodsINTREPID was a multicentre, randomised, open-label, phase IV effectiveness study comparing FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA inhaler with a clinician's choice of any approved non-ELLIPTA MITT in usual COPD clinical practice in five European countries. Primary end-point was proportion of COPD Assessment Test (CAT) responders (≥2-unit decrease in CAT score from baseline) at week 24. Secondary end-points in a subpopulation included change from baseline in forced expiratory volume in 1 s (FEV1) and percentage of patients making at least one critical error in inhalation technique at week 24. Safety was also assessed.Results3092 patients were included (FF/UMEC/VI n=1545; MITT n=1547). The proportion of CAT responders at week 24 was significantly greater with FF/UMEC/VI versus non-ELLIPTA MITT (OR 1.31, 95% CI 1.13–1.51; p<0.001) and mean change from baseline in FEV1 was significantly greater with FF/UMEC/VI (77 mL versus 28 mL; treatment difference 50 mL, 95% CI 26–73 mL; p<0.001). The percentage of patients with at least one critical error in inhalation technique was low in both groups (FF/UMEC/VI 6%; non-ELLIPTA MITT 3%). Safety profiles, including incidence of pneumonia serious adverse events, were similar between treatments.ConclusionsIn a usual clinical care setting, treatment with once-daily single-inhaler FF/UMEC/VI resulted in significantly more patients gaining health status improvement and greater lung function improvement versus non-ELLIPTA MITT.

Clinically important deterioration (CID) is a novel composite end-point (lung function, health status, exacerbations) for assessing disease stability in patients with chronic obstructive pulmonary disease (COPD).We prospectively analysed CID in the FULFIL study. FULFIL (ClinicalTrials.gov NCT02345161; randomised, double-blind, double-dummy, multicentre study) compared 24 weeks of once daily, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg with twice daily budesonide/formoterol (BUD/FOR) 400/12 μg in patients aged ≥40 years with symptomatic advanced COPD (Global Initiative for Chronic Obstructive Lung Disease group D). A subset of patients received study treatment for up to 52 weeks. Time to first CID event was assessed over 24 and 52 weeks using two approaches for the health status component: St George's Respiratory Questionnaire and COPD assessment test. FF/UMEC/VI significantly reduced the risk of a first CID event by 47–52% versus BUD/FOR in the 24- and 52-week populations using both CID definitions (p<0.001).The median time to first CID event was ≥169 days and ≤31 days with FF/UMEC/VI and BUD/FOR, respectively. Only stable patients with no CID at 24 weeks demonstrated sustained clinically important improvements in lung function and health status at 52 weeks versus those who had experienced CID.Once daily, single-inhaler FF/UMEC/VI significantly reduced the risk of CID versus twice daily BUD/FOR with a five-fold longer period without deterioration.

Ewe wastage is the combination of on-farm mortality and premature culling. Internationally, there is limited research on actual wastage incidence and causes in commercial sheep flocks. To the authors’ knowledge, this is the first study that reports both lifetime wastage and detailed annual wastage in a sample of commercial New Zealand flocks. This study utilized data collected from 13,142 ewes from four cohorts on three commercial New Zealand farms (Farm A 2010-born, Farm A 2011-born, Farm B, Farm C), during the period 2011–2017, as they aged from replacement hoggets to 6-year-old ewes (Farm A and Farm B) or 3-year-old ewes (Farm C). Data collection visits occurred at three or four key management times each year, namely pre-mating, pregnancy diagnosis, pre-lambing and weaning. At each visit, body condition score (BCS) was assessed and any ewes that were culled or had died on farm were recorded. As this was a lifetime study, each ewe was assigned an outcome and corresponding ‘exit age’. By the end of the study, all ewes that had exited their respective flocks, were classified as either prematurely culled, or dead/missing, or if still in the flock, as censored, and either the exact date or interval in which they exited the flock was recorded. Semi-parametric competing risk (premature culling vs. dead/missing), interval-censored survival models were developed to: 1. describe the association between hogget reproductive outcomes and risk of subsequent wastage, and 2. assess pre-mating BCS as a predictor of wastage in that production year. Of the 13,142 enrolled ewes, 50.4% exited their respective flocks due to premature culling and 40.0% due to on-farm dead/missing, giving a total of 90.4% that exited due to wastage. Annual mortality incidence ranged from 3.5 to 40.2%. As a hogget, wastage incidence ranged from 7.6 to 45.4%. Pregnancy or rearing a lamb as a hogget did not increase risk of subsequent wastage. In all years, pre-mating BCS was a predictor of ewe wastage, with odds of wastage lower with increasing BCS. Therefore, farmers should focus on improving pre-mating BCS to 3.5/5.0 by assessing ewe BCS at weaning, allowing poorer-BCS ewes to be managed to gain BCS before re-breeding.