Structural Predictors of Lung Function Decline in Young Smokers with Normal Spirometry.

Rationale: Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. Objectives: We hypothesized that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. Methods: We recruited 431 current smokers (median age, 39 yr; 16 pack-years smoked) and recorded symptoms using the COPD Assessment Test (CAT), spirometry, and quantitative thoracic computed tomography (QCT) scans at study entry. These scan results were compared with those from 67 never-smoking control subjects. Three hundred sixty-eight participants were followed every six months with measurement of postbronchodilator spirometry for a median of 32 months. The rate of FEV1 decline, adjusted for current smoking status, age, and sex, was related to the initial QCT appearances and symptoms, measured using the CAT. Measurements and Main Results: There were no material differences in demography or subjective CT appearances between the young smokers and control subjects, but 55.7% of the former had CAT scores greater than 10, and 24.2% reported chronic bronchitis. QCT assessments of disease probability-defined functional small airway disease, ground-glass opacification, bronchovascular prominence, and ratio of small blood vessel volume to total pulmonary vessel volume were increased compared with control subjects and were all associated with a faster FEV1 decline, as was a higher CAT score. Conclusions: Radiological abnormalities on CT are already established in young smokers with normal lung function and are associated with FEV1 loss independently of the impact of symptoms. Structural abnormalities are present early in the natural history of COPD and are markers of disease progression. Clinical trial registered with www.clinicaltrials.gov (NCT03480347).

A Pooled Analysis of Mortality in Patients with COPD Receiving Dual Bronchodilation with and without Additional Inhaled Corticosteroid.

Background: Recent studies report a lower mortality rate during treatment with long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA)/inhaled corticosteroid (ICS) versus LAMA/LABA in patients with symptomatic chronic obstructive pulmonary disease (COPD) and a history of exacerbations. Objective: We compared time to all-cause mortality with LAMA/LABA versus LAMA/LABA/ICS in patients with mild-to-very-severe COPD and a predominantly low exacerbation risk. Methods: Data were pooled from six randomized controlled trials (TONADO 1/2, DYNAGITO, WISDOM, UPLIFT and TIOSPIR; LAMA/LABA: n = 3156, LAMA/LABA/ICS: n = 11,891). Analysis was on-treatment and data were censored at 52 weeks. Patients on LAMA/LABA/ICS received ICS prior to study entry, which was not withdrawn at randomization. Patients on LAMA/LABA/ICS were propensity score (PS)-matched to patients on LAMA/LABA who had not previously received ICS; covariates included age, sex, geographical region, smoking status, post-bronchodilator forced expiratory volume in 1 second percent predicted, exacerbation history in previous year, body mass index and time since diagnosis. Time to all-cause mortality was assessed using Cox proportional hazard regression models. Results: After PS matching, 3133 patients on LAMA/LABA and 3133 patients on LAMA/LABA/ICS were analyzed. Fewer than 20% of patients reported ≥2 exacerbations in the prior year (LAMA/LABA: 19.1%; LAMA/LABA/ICS: 19.0%). There were 41 (1.3%) deaths on LAMA/LABA and 45 (1.4%) deaths on LAMA/LABA/ICS. No statistically significant difference in time to death was observed between treatment arms (hazard ratio for LAMA/LABA 1.06; 95% confidence intervals 0.68, 1.64; P = 0.806). Sensitivity analyses conducted using different covariates or in an intent-to-treat population showed similar results. Conclusion: This pooled analysis of over 6000 patients with mild-to-very-severe COPD and predominantly low exacerbation risk showed no differences in mortality with LAMA/LABA versus LAMA/LABA/ICS, suggesting that the survival benefit of triple therapy seen in some recent studies may be specific to a high-risk population. This supports current Global Initiative for Chronic Obstructive Lung Disease recommendations that triple therapy should be reserved for the subpopulations of patients who need it the most (eg, those with an eosinophilic phenotype and a high risk of exacerbations) to avoid ICS overuse.

ACO (Asthma-COPD Overlap) Is Independent from COPD: The Case in Favour.

Over the last decade interest has been shown in people with symptomatic lung disease who have features both of COPD and asthma. In this review we examine how COPD and asthma are defined and examine clinical characteristics of people defined by researchers as having asthma-COPD overlap (ACO). We look at pathological and physiological features along with symptoms and consider the impact of each diagnosis upon therapeutic management. We highlight challenges in the diagnosis and management of airway disease and the various phenotypes that could be part of ACO, in so doing suggesting ways for the clinician to manage patients with features of both asthma and COPD.

The Multifaceted Therapeutic Role of N-Acetylcysteine (NAC) in Disorders Characterized by Oxidative Stress.

Oxidative stress, which results in the damage of diverse biological molecules, is a ubiquitous cellular process implicated in the etiology of many illnesses. The sulfhydryl-containing tripeptide glutathione (GSH), which is synthesized and maintained at high concentrations in all cells, is one of the mechanisms by which cells protect themselves from oxidative stress. N-acetylcysteine (NAC), a synthetic derivative of the endogenous amino acid L-cysteine and a precursor of GSH, has been used for several decades as a mucolytic and as an antidote to acetaminophen (paracetamol) poisoning. As a mucolytic, NAC breaks the disulfide bonds of heavily cross-linked mucins, thereby reducing mucus viscosity. In vitro, NAC has antifibrotic effects on lung fibroblasts. As an antidote to acetaminophen poisoning, NAC restores the hepatic GSH pool depleted in the drug detoxification process. More recently, improved knowledge of the mechanisms by which NAC acts has expanded its clinical applications. In particular, the discovery that NAC can modulate the homeostasis of glutamate has prompted studies of NAC in neuropsychiatric diseases characterized by impaired glutamate homeostasis. This narrative review provides an overview of the most relevant and recent evidence on the clinical application of NAC, with a focus on respiratory diseases, acetaminophen poisoning, disorders of the central nervous system (chronic neuropathic pain, depression, schizophrenia, bipolar disorder, and addiction), cardiovascular disease, contrast-induced nephropathy, and ophthalmology (retinitis pigmentosa).

The effects of cancer therapies on physical fitness before oesophagogastric cancer surgery: a prospective, blinded, multi-centre, observational, cohort study.

Background: Neoadjuvant cancer treatment is associated with improved survival following major oesophagogastric cancer surgery. The impact of neoadjuvant chemo/chemoradiotherapy on physical fitness and operative outcomes is however unclear. This study aims to investigate the impact of neoadjuvant chemo/chemoradiotherapy on fitness and post-operative mortality. Methods: Patients with oesophagogastric cancer scheduled for chemo/chemoradiotherapy and surgery were recruited to a prospective, blinded, multi-centre, observational cohort study. Primary outcomes were changes in fitness with chemo/chemoradiotherapy, measured using cardiopulmonary exercise testing and its association with mortality one-year after surgery. Patients were followed up for re-admission at 30-days, in-hospital morbidity and quality of life (exploratory outcomes). Results: In total, 384 patients were screened, 217 met the inclusion criteria, 160 consented and 159 were included (72% male, mean age 65 years). A total of 132 patients (83%) underwent chemo/chemoradiotherapy, 109 (71%) underwent chemo/chemoradiotherapy and two exercise tests, 100 (63%) completed surgery and follow-up. A significant decline in oxygen uptake at anaerobic threshold and oxygen uptake peak was observed following chemo/chemoradiotherapy: -1.25ml.kg -1.min -1 (-1.80 to -0.69) and -3.02ml.kg -1.min -1 (-3.85 to -2.20); p<0.0001). Baseline chemo/chemoradiotherapy anaerobic threshold and peak were associated with one-year mortality (HR=0.72, 95%CI 0.59 to 0.88; p=0.001 and HR=0.85, 0.76 to 0.95; p=0.005). The change in physical fitness was not associated with one-year mortality. Conclusions: Chemo/chemoradiotherapy prior to oesophagogastric cancer surgery reduced physical fitness. Lower baseline fitness was associated with reduced overall survival at one-year. Careful consideration of fitness prior to chemo/chemoradiotherapy and surgery is urgently needed.

BACKGROUND: Cancer treatments such as chemotherapy and radiotherapy given to people with oesophageal and gastric cancer (also known as cancer of the food pipe/stomach) before surgery can improve survival. However, the impact such treatments have on fitness and recovery after surgery is unclear. The aim of this research was to understand the impact cancer treatments has on fitness and any complications after surgery. METHODS: Patients with oesophageal and gastric cancer (also known as cancer of the food pipe/stomach) who were being treated by cancer treatment and surgery were recruited from different hospitals in the UK. All participants were asked to undertake an exercise test to measure fitness and fill out questionnaires to measure quality of life before and after cancer treatment. Complications patients experienced after surgery, the number of patients who had to be readmitted to hospital 30 days after surgery and one-year survival was recorded. RESULTS: A total of 160 consented to participate in this study and 159 were included in the study (72% male, average age 65 years). In total, 132 patients (83%) had cancer treatment, 109 (71%) had cancer treatment and the two exercise tests and 100 (63%) had surgery and were followed-up after surgery. Study findings show that fitness reduced after cancer treatment. Patient's fitness levels at the start of the study (or before cancer treatment) were linked to one-year survival. The fall in fitness after cancer treatment was not linked to death at the one-year follow-up. CONCLUSION: Cancer treatments before oesophageal and gastric cancer reduce fitness. Patients with a lower fitness level before cancer treatment had a reduced overall survival at one-year. Careful consideration of fitness prior to such cancer treatments and surgery is urgently needed.

Use of mucolytics in COPD: A Delphi consensus study.

BACKGROUND: International guidelines recommend mucolytic agents as add-on therapy in selected patients with COPD because they may reduce exacerbations and improve health status. As the evidence varies among mucolytic agents, we used the Delphi method to assess consensus amongst an international panel of COPD experts on mucolytics use in COPD. METHODS: 53 COPD experts from 12 countries were asked to complete an online questionnaire and rate their agreement with 15 statements using a 5-point scale. The mucolytic agents evaluated were carbocysteine, erdosteine and N-acetylcysteine (NAC). Data were collected anonymously and consensus presented using descriptive statistics. RESULTS: The 47 respondents reached consensus on the statements. They agreed that regular treatment with mucolytic agents effectively reduces the frequency of exacerbations, reduces the duration of mild-to-moderate exacerbations, and can increase the time to first exacerbation and symptom-free time in COPD patients. Consensus was consistently highest for erdosteine. The experts agreed that all three mucolytics display antioxidant and anti-inflammatory activity. Erdosteine and NAC were thought to improve the efficacy of some classes of antibacterial drugs. All three mucolytics were considered effective for the short-term treatment of symptoms of acute exacerbations when added to other drugs. The panel agreed that approved doses of mucolytic agents have favorable side-effect profiles and can be recommended for regular use in patients with a bronchitic phenotype. CONCLUSIONS: Consensus findings support the wider use of mucolytic agents as add-on therapy for COPD. However, the differences in pharmacological actions and clinical effectiveness must be considered when deciding which mucolytic to use.

FEV1 is a stronger mortality predictor than FVC in patients with moderate COPD and with an increased risk for cardiovascular disease.

Purpose: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. Impaired lung function is associated with heightened risk for death, cardiovascular events, and COPD exacerbations. However, it is unclear if forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) differ in predictive value. Patients and Methods: Data from 16,485 participants in the Study to Understand Mortality and Morbidity (SUMMIT) in COPD were analyzed. Patients were grouped into quintiles for each lung function parameter (FEV1 %predicted, FVC %predicted, FEV1/FVC). The four highest quintiles (Q2-Q5) were compared to the lowest (Q1) to assess their relationship with all-cause mortality, cardiovascular events, and moderate-to-severe and severe exacerbations. Cox-regression was used, adjusted for age, sex, ethnicity, body-mass index, smoking status, previous exacerbations, cardiovascular disease, treatment, and modified Medical Research Council dyspnea score. Results: Compared to Q1 (<53.5% FEV1 predicted), increasing FEV1 quintiles (Q2 53.5-457.5% predicted, Q3 57.5-461.6% predicted, Q4 61.6-465.8% predicted, and Q5 ≥65.8%) were all associated with significantly decreased all-cause mortality (20% (4-34%), 28% (13-40%), 23% (7-36%), and 30% (15-42%) risk reduction, respectively). In contrast, a significant risk reduction (21% (4-35%)) was seen only between Q1 and Q5 quintiles of FVC. Neither FEV1 nor FVC was associated with cardiovascular risk. Increased FEV1 and FEV1/FVC quintiles were also associated with the reduction of moderate-to-severe and severe exacerbations while, surprisingly, the highest FVC quintile was related to the heightened exacerbation risk (28% (8-52%) risk increase). Conclusion: Our results suggest that FEV1 is a stronger predictor for all-cause mortality than FVC in moderate COPD patients with heightened cardiovascular risk and that subjects with moderate COPD have very different risks.

Impact of smoking status and concomitant medications on the effect of high-dose N-acetylcysteine on chronic obstructive pulmonary disease exacerbations: A post-hoc analysis of the PANTHEON study.

BACKGROUND: N-acetylcysteine (NAC) 600 mg twice daily is a well-tolerated oral antioxidant mucolytic that reduces the risk of moderate to severe chronic obstructive pulmonary disease (COPD) exacerbations. PANTHEON was one of the largest studies to evaluate NAC in COPD. It recruited current, ex- and never-smokers, concomitantly treated with other medications, and used a symptom-based definition of COPD exacerbations rather than the conventional healthcare resource utilisation (HCU) criteria. METHODS: This manuscript reports post-hoc analyses of the PANTHEON dataset investigating whether smoking status or use of concomitant medications influenced the efficacy of NAC in terms of reducing exacerbations, defined according to HCU. RESULTS: Compared with placebo (N = 482), NAC (N = 482) reduced the rate of HCU events by 20% (p = 0.0027), with a larger effect in current/ex-smokers (23%; p < 0.01). In patients receiving NAC and long-acting inhaled bronchodilator(s) but no ICS, there was a 60% reduction in the rate of exacerbations compared to those receiving placebo, long-acting bronchodilator(s) and ICS (p < 0.0001). CONCLUSIONS: Overall, these post-hoc hypothesis-generating analyses confirm that NAC reduces the rate of COPD exacerbations, particularly in patients with COPD who have a significant smoking history, and in those not treated with ICS. NAC may provide an alternative to ICS-containing combinations in these patient subgroups. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trials Registry, ChiCTR-TRC-09000460.

Determinants of Response to Roflumilast in Severe Chronic Obstructive Pulmonary Disease. Pooled Analysis of Two Randomized Trials.

RATIONALE: Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations. Further characterization of patients most likely to benefit is warranted. OBJECTIVES: Define characteristics that most robustly identify patients who derive greatest exacerbation risk reduction with roflumilast. METHODS: Predefined, pooled analyses of REACT (Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment; NCT01329029) and RE2SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy; NCT01443845) multicenter, randomized, double-blind, placebo-controlled studies. The primary endpoint was rate of moderate or severe exacerbations per patient per year. MEASUREMENTS AND MAIN RESULTS: In the overall intention-to-treat population (n = 4,287), roflumilast reduced moderate or severe exacerbations by 12.3% (rate ratio, 0.88, 95% confidence interval, 0.80-0.97; P = 0.0086) and severe exacerbations by 16.1% (0.84; 0.71-0.99; P = 0.0409) versus placebo. The reduction in moderate or severe exacerbations with roflumilast was most pronounced in patients who had been hospitalized for an exacerbation in the prior year (0.74; 0.63-0.88; P = 0.0005); had more than two exacerbations in the prior year (0.79; 0.65-0.96; P = 0.0160); or had baseline eosinophils ≥150 cells/µl (0.81; 0.71-0.93; P = 0.0020), ≥150 to <300 cells/µl (0.84; 0.71-0.98; P = 0.0282), or ≥300 cells/µl (0.77; 0.61-0.97; P = 0.0264). Similar subgroup results were noted for severe exacerbations. In patients with prior hospitalization and higher baseline blood eosinophil concentrations, roflumilast reduced moderate or severe exacerbations by 34.5% at ≥150 cells/µl (0.65; 0.52-0.82; P = 0.0003) and 42.7% at ≥300 cells/µl (0.57; 0.37-0.88; P = 0.0111) versus placebo. CONCLUSIONS: This prespecified, pooled analysis confirms the benefit of roflumilast in decreasing exacerbations in patients with prior hospitalization for exacerbation, greater exacerbation frequency, and higher (≥150 cells/µl, ≥150 to <300 cells/µl, or ≥300 cells/µl) baseline blood eosinophil count.

Tiotropium and olodaterol in the prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO): a double-blind, randomised, parallel-group, active-controlled trial.

BACKGROUND: Combinations of long-acting bronchodilators are recommended to reduce the rate of chronic obstructive pulmonary disease (COPD) exacerbations. It is unclear whether combining olodaterol, a long-acting beta-agonist, with tiotropium, a long-acting anti-muscarinic, reduces the rate of exacerbations compared with tiotropium alone. METHODS: This 52-week, double-blind, randomised, parallel-group, active-controlled trial randomly assigned (1:1) patients with COPD with a history of exacerbations using a randomised block design to receive tiotropium-olodaterol 5 µg-5 µg or tiotropium 5 µg once daily. Patients using inhaled corticosteroids continued this therapy. Treatment was masked to patients, investigators, and those involved in analysing the data. The primary endpoint was the rate of moderate and severe COPD exacerbations from the first dose of medication until 1 day after last drug administration. The primary analysis included all randomly assigned patients who received any dose of study medication but were not from a site excluded due to on-site protocol violations. The trial is registered with ClinicalTrials.gov, number NCT02296138. FINDINGS: Overall, 9009 patients were screened from 818 centres in 51 countries. We recruited 7880 patients between Jan 22, 2015 and March 7, 2016 (mean age 66·4 years [SD 8·5], 5626 [71%] were men, mean FEV1 percent predicted 44·5% [SD 27·7]): 3939 received tiotropium-olodaterol and 3941 tiotropium. The rate of moderate and severe exacerbations was lower with tiotropium-olodaterol than tiotropium (rate ratio [RR] 0·93, 99% CI 0·85-1·02; p=0·0498), not meeting the targeted 0·01 significance level. The proportion of patients reporting adverse events was similar between treatments. INTERPRETATION: Combining tiotropium and olodaterol did not reduce exacerbation rate as much as expected compared with tiotropium alone. FUNDING: Boehringer Ingelheim International GmbH.

Demographic Characteristics and Clinical Outcomes in Patients from Latin America Versus the Rest of the World: A TIOSPIR® Post-Hoc Analysis.

INTRODUCTION: Geographical variations may impact outcomes in chronic obstructive pulmonary disease (COPD). We evaluated differences in baseline characteristics and outcomes between patients enrolled in Latin America compared with the rest of the world (RoW) in the TIOtropium Safety and Performance In Respimat® (TIOSPIR®) trial. METHODS: TIOSPIR®, a 2-3-year, randomized, double-blind trial (n=17116; treated set), compared safety and efficacy of once-daily tiotropium Respimat® 5 and 2.5µg with tiotropium HandiHaler® 18µg. This post-hoc analysis pooled data from all treatment arms to assess mortality, exacerbations, cardiac events, and serious adverse events (SAEs) between both regions. RESULTS: At baseline, patients enrolled in Latin America (n=1000) versus RoW (n=16116) were older, with higher pack-years of smoking history and more exacerbations, but less cardiac history. In this analysis, patients in Latin America versus RoW had an increased risk of death (hazard ratio [HR] [95% confidence interval (CI)]: 1.52 [1.24-1.86]; P<.0001) or moderate-to-severe exacerbation (HR [95% CI]: 1.29 [1.18-1.41]; P<.0001), but a lower risk of severe exacerbation (HR [95% CI]: 0.82 [0.68-0.98]; P=.0333). SAE rates in Latin America were lower versus RoW (incidence rate ratio [IRR] [95% CI]: 0.82 [0.72-0.92]), including cardiac disorders (IRR [95% CI]: 0.68 [0.48-0.97]). Risk of major adverse cardiovascular events were similar (HR [95% CI]: 0.99 [0.71-1.40]; P=.9677). CONCLUSIONS: TIOSPIR® patients in Latin America had a higher risk of death or moderate-to-severe exacerbation, but a lower risk of severe exacerbation than those in RoW. Geographical differences may impact outcomes in COPD trials.

Sarcopenic Obesity, Functional Outcomes, and Systemic Inflammation in Patients With Chronic Obstructive Pulmonary Disease.

BACKGROUND: Both loss of muscle mass (ie, sarcopenia) and obesity adversely impact clinically important outcomes in patients with chronic obstructive pulmonary disease (COPD). Currently, there are only a few studies in patients with COPD with sarcopenia and concurrent obesity, termed sarcopenic obesity (SO). OBJECTIVE: To explore the effects of SO on exercise capacity, health status, and systemic inflammation in COPD. DESIGN/SETTINGS/PARTICIPANTS: Baseline data collected from a total of 2548 participants (2000 patients with COPD, mean age (SD), 63.5 (7.1) years; and 548 controls, 54.8 (9.0) years) from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study, a multicenter longitudinal observational study, were used. MEASUREMENTS: All participants were divided into 4 body composition phenotypes using bioelectrical impedance analysis: (1) normal body composition, (2) obesity, (3) sarcopenia, and (4) SO. In patients with COPD, the 6-minute walking distance, disease-specific health status, and plasma inflammatory markers were compared among the respective body composition groups. RESULTS: Patients with COPD were 3 times more likely to present with SO compared with controls without COPD (odds ratio [OR] 3.3, 95% confidence interval [CI] 2.0-5.4, P < .001). In patients with COPD, SO was related to reduced 6-minute walking distance (-28.0 m, 95% CI -45.6 to -10.4), P < .01) and to higher systemic inflammatory burden (an elevation of at least 2 inflammatory markers, OR 1.6, 95% CI 1.1-2.5, P = .028) compared with the normal body composition group after adjustments for age, sex, smoking, body mass index, and airflow limitation. CONCLUSIONS: Our findings suggest that SO is associated with worse physical performance and higher systemic inflammatory burden compared with other body composition phenotypes in patients with COPD. TRIAL REGISTRY: ClinicalTrials.gov no. NCT00292552.

Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) often coexists with cardiovascular disease. Treatments for airflow limitation might improve survival and both respiratory and cardiovascular outcomes. The aim of this study was to assess whether inhaled treatment with a combined treatment of the corticosteroid, fluticasone furoate, and the long-acting ß agonist, vilanterol could improve survival compared with placebo in patients with moderate COPD and heightened cardiovascular risk. METHODS: In this double-blind randomised controlled trial (SUMMIT) done in 1368 centres in 43 countries, eligible patients were aged 40-80 years and had a post-bronchodilator forced expiratory volume in 1 s (FEV1) between 50% and 70% of the predicted value, a ratio of post-bronchodilator FEV1 to forced vital capacity (FVC) of 0·70 or less, a smoking history of at least 10 pack-years, and a score of 2 or greater on the modified Medical Research Council dyspnoea scale. Patients had to have a history, or be at increased risk, of cardiovascular disease. Enrolled patients were randomly assigned (1:1:1:1) through a centralised randomisation service in permuted blocks to receive once daily inhaled placebo, fluticasone furoate (100 µg), vilanterol (25 µg), or the combination of fluticasone furoate (100 µg) and vilanterol (25 µg). The primary outcome was all-cause mortality, and secondary outcomes were on-treatment rate of decline in forced expiratory volume in 1 s (FEV1) and a composite of cardiovascular events. Safety analyses were performed on the safety population (all patients who took at least one dose of study drug) and efficacy analyses were performed on the intention-to-treat population (safety population minus sites excluded with Good Clinical Practice violations). This study is registered with ClinicalTrials.gov, number NCT01313676. FINDINGS: Between Jan 24, 2011, and March 12, 2014, 23 835 patients were screened, of whom 16 590 were randomised. 16 485 patients were included in the intention-to-treat efficacy population; 4111 in the placebo group, 4135 in the fluticasone furoate group, 4118 in the vilanterol group, and 4121 in the combination group. Compared with placebo, all-cause mortality was unaffected by combination therapy (hazard ratio [HR] 0·88 [95% CI 0·74-1·04]; 12% relative reduction; p=0·137) or the components (fluticasone furoate, HR 0·91 [0·77-1·08]; p=0·284; vilanterol, 0·96 [0·81-1·14]; p=0·655), and therefore secondary outcomes should be interpreted with caution. Rate of decline in FEV1 was reduced by combination therapy (38 mL per year [SE 2·4] vs 46 mL per year [2·5] for placebo, difference 8 mL per year [95% CI 1-15]) with similar findings for fluticasone furoate (difference 8 mL per year [95% CI 1-14]), but not vilanterol (difference -2 mL per year [95% CI -8 to 5]). Combination therapy had no effect on composite cardiovascular events (HR 0·93 [95% CI 0·75-1·14]) with similar findings for fluticasone furoate (0·90 [0·72-1·11]) and vilanterol (0·99 [0·80-1·22]). All treatments reduced the rate of moderate and severe exacerbation. No reported excess risks of pneumonia (5% in the placebo group, 6% in the combination group, 5% in the fluticasone furoate group, and 4% in the vilanterol group) or adverse cardiac events (17% in the placebo group, 18% in the combination group, and 17% in the fluticasone furoate group, and 17% in the vilanterol group) were noted in the treatment groups. INTERPRETATION: In patients with moderate COPD and heightened cardiovascular risk, treatment with fluticasone furoate and vilanterol did not affect mortality or cardiovascular outcomes, reduced exacerbations, and was well tolerated. Fluticasone furoate, alone or in combination with vilanterol, seemed to reduce FEV1 decline. FUNDING: GlaxoSmithKline.

Blood eosinophils as a marker of response to inhaled corticosteroids in COPD.

Identification of a biomarker that predicts response to inhaled corticosteroids (ICS) would help evaluate the risk/benefit profile of ICS in chronic obstructive pulmonary disease (COPD) and guide treatment.The ISOLDE study randomised 751 patients (mean post-bronchodilator forced expiratory volume in 1 s (FEV1) 1.4 L: 50% predicted normal) to fluticasone propionate 500 µg twice daily or placebo for 3 years, finding no difference in FEV1 rate of decline between treatments (p=0.16) and a significant reduction in median exacerbation rate with fluticasone propionate versus placebo (p=0.026). We re-analysed ISOLDE results by baseline blood eosinophil count to investigate whether eosinophil level predicts ICS benefit.Patients with eosinophils <2% (n=456) had a similar rate of post-bronchodilator FEV1 decline with fluticasone propionate as placebo (-2.9 mL·year(-1); p=0.688). With eosinophils ≥2% (n=214), the rate of decline decreased by 33.9 mL·year(-1) with fluticasone propionate versus placebo (p=0.003). Exacerbation rate reduction on ICS for fluticasone propionate versus placebo was higher in the eosinophil <2% group compared with the ≥2% group; time-to-first moderate/severe exacerbation was not different between treatments in either group.A baseline blood eosinophil count of ≥2% identifies a group of COPD patients with slower rates of decline in FEV1 when treated with ICS: prospective testing of this hypothesis is now warranted.

The Association Between Heroin Inhalation and Early Onset Emphysema.

BACKGROUND: Inhalation/smoking has become the most common method of recreational opiate consumption in the United Kingdom and other countries. Although some heroin smokers appear to develop COPD, little is known about the association. METHODS: We present data from a cohort of 73 heroin smokers with clinician-diagnosed and spirometrically confirmed COPD, seen within our clinical service, where symptoms developed before the age of 40 years. RESULTS: The whole group mean age at diagnosis was 41 years, subjects had smoked heroin for 14 years, and mean FEV1 was 1.08 L (31.5% predicted), with mean FEV1/FVC of 0.4. No subject was found to have severe α1-antitrypsin deficiency. Forty-four subjects had either a high-resolution CT (HRCT) scan (32) or measurement of lung diffusion (12). Overall HRCT scan emphysema score averaged across the upper, middle, and lower part of the lung was 2.3 (5%-25% emphysema), with 47% subjects having an upper lobe emphysema score ≥ 3 (25%-50% emphysema). Median diffusing capacity of the lung for carbon monoxide was 48% of predicted value. CONCLUSIONS: Recreational smoking of heroin appears to lead to early onset COPD with a predominant emphysema phenotype. This message is important to both clinicians and the public, and targeted screening and education of this high-risk population may be justified.

Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial.

BACKGROUND: Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease. Its effect in patients using fixed combinations of inhaled corticosteroids and longacting ß2 agonists is unknown. We postulated that roflumilast would reduce exacerbations in patients with severe chronic obstructive pulmonary disease at risk for exacerbations, even in combination with inhaled corticosteroid and longacting ß2 agonist treatment. METHODS: For this 1-year double-blind, placebo-controlled, parallel group, multicentre, phase 3-4 trial, the Roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy (REACT) study, we enrolled patients with severe chronic obstructive pulmonary disease from 203 centres (outpatient clinics, hospitals, specialised pulmonologists, and family doctors) in 21 countries. Eligible patients were 40 years of age or older with a smoking history of at least 20 pack-years and a diagnosis of chronic obstructive pulmonary disease with severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year. We used a computerised central randomisation system to randomly assign patients in a 1:1 ratio to the two treatment groups: roflumilast 500 µg or placebo given orally once daily together with a fixed inhaled corticosteroid and longacting ß2 agonist combination. Background tiotropium treatment was allowed. All patients and investigators were masked to group assignment. The primary outcome was the rate of moderate to severe chronic obstructive pulmonary disease exacerbations per patient per year, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329029. FINDINGS: Between April 3, 2011, and May 27, 2014, we enrolled 1945 eligible participants and randomly assigned 973 to the roflumilast group and 972 to the placebo group. The rate of moderate-to-severe chronic obstructive pulmonary disease exacerbations was 13·2% lower in the roflumilast group than in the placebo group according to a Poisson regression analysis (roflumilast 0·805 vs placebo 0·927; rate ratio [RR] 0·868 [95% CI 0·753-1·002], p=0·0529), and 14·2% lower according to a predefined sensitivity analysis using negative binomial regression (0·823 vs 0·959; 0·858 [0·740-0·995], p=0·0424). Adverse events were reported by 648 (67%) of 968 patients receiving roflumilast and by 572 (59%) of 967 patients in the placebo group; adverse event-associated patient withdrawal from the study was also more common in the roflumilast group (104/968 [11%]) than in the placebo group (52/967 [5%]). The most frequently reported serious adverse events were chronic obstructive pulmonary disease exacerbations and pneumonia, and 17 (1·8%) deaths occurred in the roflumilast group compared with 18 (1·9%) in the placebo group. INTERPRETATION: Our findings suggest that roflumilast reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of frequent and severe exacerbations despite inhaled corticosteroid and longacting ß2 agonist therapy, even in combination with tiotropium. FUNDING: Takeda.

Evaluating the role of inflammation in chronic airways disease: the ERICA study.

Extrapulmonary manifestations are recognized to be of increasing clinical importance in Chronic Obstructive Pulmonary disease. To investigate cardiovascular and skeletal muscle manifestations of COPD, we developed a unique UK consortium funded by the Technology Strategy Board and Medical Research Council comprising industry in partnership with 5 academic centres. ERICA (Evaluating the Role of Inflammation in Chronic Airways disease) is a prospective, longitudinal, observational study investigating the prevalence and significance of cardiovascular and skeletal muscle manifestations of COPD in 800 subjects. Six monthly follow up will assess the predictive value of plasma fibrinogen, cardiovascular abnormalities and skeletal muscle weakness for death or hospitalization. As ERICA is a multicentre study, to ensure data quality we sought to minimise systematic observer error due to variations in investigator skill, or adherence to operating procedures, by staff training followed by assessment of inter- and intra-observer reliability of the four key measurements used in the study: pulse wave velocity (PWV), carotid intima media thickness (CIMT), quadriceps maximal voluntary contraction force (QMVC) and 6-minute walk distance (6MWT). This report describes the objectives and methods of the ERICA trial, as well as the inter- and intra-observer reliability of these measurements.