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

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/)

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

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)

Stress triggering in thrust and subduction earthquakes and stress interaction between the southern San Andreas and nearby thrust and strike-slip faults

Author Posting. © American Geophysical Union, 2004. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 109 (2004): B02303, doi:10.1029/2003JB002607.We argue that key features of thrust earthquake triggering, inhibition, and clustering can be explained by Coulomb stress changes, which we illustrate by a suite of representative models and by detailed examples. Whereas slip on surface-cutting thrust faults drops the stress in most of the adjacent crust, slip on blind thrust faults increases the stress on some nearby zones, particularly above the source fault. Blind thrusts can thus trigger slip on secondary faults at shallow depth and typically produce broadly distributed aftershocks. Short thrust ruptures are particularly efficient at triggering earthquakes of similar size on adjacent thrust faults. We calculate that during a progressive thrust sequence in central California the 1983 Mw = 6.7 Coalinga earthquake brought the subsequent 1983 Mw = 6.0 Nuñez and 1985 Mw = 6.0 Kettleman Hills ruptures 10 bars and 1 bar closer to Coulomb failure. The idealized stress change calculations also reconcile the distribution of seismicity accompanying large subduction events, in agreement with findings of prior investigations. Subduction zone ruptures are calculated to promote normal faulting events in the outer rise and to promote thrust-faulting events on the periphery of the seismic rupture and its downdip extension. These features are evident in aftershocks of the 1957 Mw = 9.1 Aleutian and other large subduction earthquakes. We further examine stress changes on the rupture surface imparted by the 1960 Mw = 9.5 and 1995 Mw = 8.1 Chile earthquakes, for which detailed slip models are available. Calculated Coulomb stress increases of 2–20 bars correspond closely to sites of aftershocks and postseismic slip, whereas aftershocks are absent where the stress drops by more than 10 bars. We also argue that slip on major strike-slip systems modulates the stress acting on nearby thrust and strike-slip faults. We calculate that the 1857 Mw = 7.9 Fort Tejon earthquake on the San Andreas fault and subsequent interseismic slip brought the Coalinga fault ~1 bar closer to failure but inhibited failure elsewhere on the Coast Ranges thrust faults. The 1857 earthquake also promoted failure on the White Wolf reverse fault by 8 bars, which ruptured in the 1952 Mw = 7.3 Kern County shock but inhibited slip on the left-lateral Garlock fault, which has not ruptured since 1857. We thus contend that stress transfer exerts a control on the seismicity of thrust faults across a broad spectrum of spatial and temporal scales.J. L. was supported by the National Science Foundation through grant NSFEAR0003888; R. S. gratefully acknowledges funding from Swiss Re

Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis

Inhaled corticosteroids are important in the management of chronic obstructive pulmonary disease (COPD), but can slightly increase the risk of pneumonia in patients with moderate-to-severe COPD. Patients with circulating eosinophil counts of 2% or more of blood leucocytes respond better to inhaled corticosteroids than do those with counts of less than 2% and it was therefore postulated that blood eosinophil count might also have an effect on the risk of pneumonia in patients with COPD. In this post-hoc meta-analysis, we investigate whether a 2% threshold can identify patients who differ in their risk of pneumonia, irrespective of inhaled corticosteroid treatment.From the GlaxoSmithKline trial registry, we selected randomised, double-blind, clinical trials of patients with COPD that had: inhaled corticosteroid arms (fluticasone propionate and salmeterol or fluticasone furoate and vilanterol); a control arm (not given inhaled fluticasone); and pre-randomisation measurements of blood eosinophil counts and were of at least 24 weeks in duration. With use of specified terms from the Medical Dictionary for Regulatory Activities we identified pneumonia adverse events in patient-level data. We calculated number of patients with pneumonia events, stratified by baseline blood eosinophil count (&lt;2% vs ≥2% of blood leucocytes) and whether or not patients had received inhaled corticosteroids.We identified ten trials (conducted between 1998 and 2011), with eosinophil count data available for 10 861 patients with COPD. 4043 patients had baseline blood eosinophil counts of less than 2% and 6818 patients had baseline blood eosinophil counts of 2% or more. 149 (3·7%) patients with counts less than 2% had one or more pneumonia adverse events compared with 215 (3·2%) with counts of 2% or more (hazard ratio [HR] 1·31; 95% CI 1·06-1·62). In patients not treated with inhaled corticosteroids, 40 (3·8%) patients with less than 2% blood eosinophil counts had a pneumonia event versus 48 (2·4%) with 2% or more blood eosinophils (HR 1·53; 95% CI 1·01-2·31). In patients treated with inhaled corticosteroids, events occurred in 107 (4·5%) versus 164 (3·9%; HR 1·25; 95% CI 0·98-1·60), respectively.Using 2% baseline eosinophil count as a threshold, patients with COPD with lower blood eosinophil counts had more pneumonia events than did those with higher counts. The magnitude of this increased risk was small and should be further explored in large, prospective studies. These data should be considered when making treatment decisions, alongside existing evidence that patients with COPD and baseline blood eosinophil counts less than 2% have a poorer response to inhaled corticosteroids.GlaxoSmithKline

Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis

Inhaled corticosteroids are important in the management of chronic obstructive pulmonary disease (COPD), but can slightly increase the risk of pneumonia in patients with moderate-to-severe COPD. Patients with circulating eosinophil counts of 2% or more of blood leucocytes respond better to inhaled corticosteroids than do those with counts of less than 2% and it was therefore postulated that blood eosinophil count might also have an effect on the risk of pneumonia in patients with COPD. In this post-hoc meta-analysis, we investigate whether a 2% threshold can identify patients who differ in their risk of pneumonia, irrespective of inhaled corticosteroid treatment.From the GlaxoSmithKline trial registry, we selected randomised, double-blind, clinical trials of patients with COPD that had: inhaled corticosteroid arms (fluticasone propionate and salmeterol or fluticasone furoate and vilanterol); a control arm (not given inhaled fluticasone); and pre-randomisation measurements of blood eosinophil counts and were of at least 24 weeks in duration. With use of specified terms from the Medical Dictionary for Regulatory Activities we identified pneumonia adverse events in patient-level data. We calculated number of patients with pneumonia events, stratified by baseline blood eosinophil count (<2% vs ≥2% of blood leucocytes) and whether or not patients had received inhaled corticosteroids.We identified ten trials (conducted between 1998 and 2011), with eosinophil count data available for 10 861 patients with COPD. 4043 patients had baseline blood eosinophil counts of less than 2% and 6818 patients had baseline blood eosinophil counts of 2% or more. 149 (3·7%) patients with counts less than 2% had one or more pneumonia adverse events compared with 215 (3·2%) with counts of 2% or more (hazard ratio [HR] 1·31; 95% CI 1·06-1·62). In patients not treated with inhaled corticosteroids, 40 (3·8%) patients with less than 2% blood eosinophil counts had a pneumonia event versus 48 (2·4%) with 2% or more blood eosinophils (HR 1·53; 95% CI 1·01-2·31). In patients treated with inhaled corticosteroids, events occurred in 107 (4·5%) versus 164 (3·9%; HR 1·25; 95% CI 0·98-1·60), respectively.Using 2% baseline eosinophil count as a threshold, patients with COPD with lower blood eosinophil counts had more pneumonia events than did those with higher counts. The magnitude of this increased risk was small and should be further explored in large, prospective studies. These data should be considered when making treatment decisions, alongside existing evidence that patients with COPD and baseline blood eosinophil counts less than 2% have a poorer response to inhaled corticosteroids.GlaxoSmithKline