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.
Clinically important deterioration (CID) in chronic obstructive pulmonary disease (COPD) is a novel composite endpoint that assesses disease stability. The association between short-term CID and ...future economic and quality of life (QoL) outcomes has not been previously assessed. This analysis considers 3-year data from the TOwards a Revolution in COPD Health (TORCH) study, to examine this question.
This post hoc analysis of TORCH (NCT00268216) compared costs and utilities at 3 years among patients without CID (CID-) and with CID (CID+) at 24 weeks. A positive CID status was defined as either: a deterioration in forced expiratory volume in 1 second (FEV
) of ≥100 mL from baseline; or a ≥4-unit increase from baseline in St George's Respiratory Questionnaire (SGRQ) total score; or the incidence of a moderate/severe exacerbation. Patients from all treatment arms were included. Utility change was based on the EQ-5D utility index. Costs were based on healthcare resource utilization from 24 weeks to end of follow-up combined with unit costs for the UK (2016 GBP), and reported as per patient per year (PPPY). Adjusted estimates were generated controlling for baseline characteristics, treatment assignment, and number of CID criteria met.
Overall, 3,769 patients completed the study and were included in the analysis (stable CID- patients, n=1,832; unstable CID+ patients, n=1,937). At the end of follow-up, CID- patients had higher mean (95% confidence interval CI) utility scores than CID+ patients (0.752 0.738, 0.765 vs 0.697 0.685, 0.71; difference +0.054;
<0.001), and lower costs PPPY (£538 vs £916; difference: £378 95% CI: £244, £521;
<0.001). The cost differential was primarily driven by the difference in general hospital ward days (
=0.003).
This study demonstrated that achieving early stability in COPD by preventing short-term CID is associated with better preservation of future QoL alongside reduced healthcare service costs.
Assessing clinically important measures of disease progression is essential for evaluating therapeutic effects on disease stability in chronic obstructive pulmonary disease (COPD). This analysis ...assessed whether providing additional bronchodilation with the long-acting muscarinic antagonist umeclidinium (UMEC) to patients treated with inhaled corticosteroid (ICS)/long-acting β
-agonist (LABA) therapy would improve disease stability compared with ICS/LABA therapy alone.
This integrated post hoc analysis of four 12-week, randomized, double-blind trials (NCT01772134, NCT01772147, NCT01957163, NCT02119286) compared UMEC 62.5 µg with placebo added to open-label ICS/LABA in symptomatic patients with COPD (modified Medical Research Council dyspnea scale score ≥ 2). A clinically important deterioration (CID) was defined as: a decrease from baseline of ≥ 100 mL in trough forced expiratory volume in 1 s (FEV
), an increase from baseline of ≥ 4 units in St George's Respiratory Questionnaire (SGRQ) total score, or a moderate/severe exacerbation. Risk of a first CID was evaluated in the intent-to-treat (ITT) population and in patients stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) classification, exacerbation history and type of ICS/LABA therapy. Adverse events (AEs) were also assessed.
Overall, 1637 patients included in the ITT population received UMEC + ICS/LABA (n = 819) or placebo + ICS/LABA (n = 818). Additional bronchodilation with UMEC reduced the risk of a first CID by 45-58% in the ITT population and all subgroups analyzed compared with placebo (all p < 0.001). Improvements were observed in reducing FEV
(69% risk reduction; p < 0.001) and exacerbation (47% risk reduction; p = 0.004) events in the ITT population. No significant reduction in risk of a SGRQ CID was observed. AE incidence was similar between treatment groups.
Symptomatic patients with COPD receiving ICS/LABA experience frequent deteriorations. Additional bronchodilation with UMEC significantly reduced the risk of CID and provided greater short-term stability versus continued ICS/LABA therapy in these patients.
GlaxoSmithKline (study number: 202067). Plain language summary available for this article.
Background and aims: Short-acting bronchodilators are normally used as supplemental relief medication for breakthrough symptoms in COPD patients. The objective of this cross-sectional study was to ...assess if more frequent vs infrequent use of relief medication in maintenance-treated COPD patients, split by the severity dyspnea, was associated with an increase in the overall disease burden.
Methods: A population-based cross-sectional survey (Adelphi DSP) was conducted among patients with COPD in five European countries. Information was collected on demographic and clinical characteristics, reliever inhaler use, dyspnea (mMRC), health status (CAT, EQ-5D), sleep quality (JSEQ) and healthcare resource use including moderate-severe COPD exacerbations, physician visits, COPD medications and other COPD related resources. The humanistic and economic burden was compared between patients with infrequent reliever use (<1 occasion/week) and more frequent use (≥ 1 occasion/week). The association between increased reliever use and economic burden was also examined after matching patients based on propensity-scores balancing demographic and disease burden characteristics.
Results: Among the 1373 COPD patients prescribed a reliever inhaler, 29% reported using reliever medication ≥1 occasion/week. In the unmatched cohort, more frequent reliever use (n = 377) compared to infrequent use (n = 996) was linked to poorer health status (CAT: 25.7 vs 20.0; p < .0001; EQ-5D-3L: 0.63 vs 0.82; p < .0001) and poorer sleep quality (JSEQ: 8.6 vs 4.6 units; p < .0001). More frequent reliever use was also associated with higher annual rates of moderate/severe exacerbations (1.6 vs 1.0 events/year; p < .0001) and respiratory specialist visits (2.8 vs 2.2 events/year; p = .0001). In the propensity-score matched population, more frequent reliever use was also associated with significantly higher annual costs for COPD management (€5,034 vs €3,705, p = .0327) compared to patients with infrequent reliever use.
Conclusion: In moderate-to-severe COPD, more frequent reliever use is associated with increased exacerbation risk and increased management costs.
Introduction
Dyspnoea is a common symptom of chronic obstructive pulmonary disease (COPD) that has a significant direct impact on patients’ respiratory health status and contributes substantially to ...the economic burden of the disease. The objective of this study was to report on the prevalence of dyspnoea and its cost impact among patients with COPD in five European countries (France, Germany, Italy, Spain and the UK).
Methods
A population-based cross-sectional survey (Respiratory Disease-Specific Programme, Adelphi Real World) was conducted among 2531 patients with COPD and their treating physicians. Information was collected on demographic and clinical characteristics, dyspnoea modified Medical Research Council (mMRC) scale, health status COPD Assessment Test (CAT), EuroQol (EQ-5D-3L), sleep Jenkins Sleep Evaluation Questionnaire (JSEQ), and healthcare resource use including moderate-to-severe COPD exacerbations, physician visits, COPD medications, and other COPD-related resources. The humanistic and economic burden was derived from two cohorts based on their level of dyspnoea (mMRC <2 vs. mMRC ≥2) who were matched by propensity scores to balance their demographic and disease burden characteristics.
Results
Moderate-to-severe dyspnoea (mMRC ≥2) was highly prevalent across all countries, ranging from 39.5% in France to 60.2% in the UK. Overall in the unmatched cohorts, mMRC ≥2 (
n
= 1199) was associated with more comorbidities and more frequent exacerbations (
>
2/year) compared to patients with mMRC <2 (
n
= 1332). Descriptive analysis indicated that the patient cohort with worse dyspnoea had poorer health status (CAT: 25.1 vs. 16.2;
P
< 0.0001), poorer sleep (JSEQ: 7.1 vs. 3.8;
P
< 0.0001), and poorer quality of life (EQ-5D-3L: 0.66 vs. 0.88;
P
< 0.0001). These findings were replicated in each of the five EU countries. In the propensity score-matched population balanced for non-dyspnoeic severity parameters, patients with worse dyspnoea had significantly higher annual costs for COPD management (€4372 vs. €2031,
P
< 0.0001).
Conclusion
Moderate-to-severe dyspnoea is highly prevalent in patients with COPD across the five European countries studied. It is associated with a significant disease burden and more than doubles the economic burden on health care systems.
Funding
GlaxoSmithKline (Study number HO-15-15223).
Introduction
Comparative data on the efficacies of long-acting muscarinic antagonist (LAMA) and long-acting β
2
-agonist (LABA) combinations for the treatment of moderate-to-very-severe chronic ...obstructive pulmonary disease (COPD) are limited. The aim of this Bayesian network meta-analysis (NMA) is to assess the relative efficacies of available open combinations (delivered via separate inhalers) and fixed-dose combinations (FDCs, delivered via a single inhaler).
Methods
We conducted a systematic literature review with the aim of identifying randomized controlled trials (RCTs) of ≥8-week duration in adults aged ≥40 years with COPD that compared LAMA + LABA combinations with each other, with tiotropium (TIO), or with placebo. Data on changes from baseline in trough forced expiratory volume in 1 s (FEV
1
) and on St George’s Respiratory Questionnaire (SGRQ) total score, the Transition Dyspnea Index (TDI) focal score, and rescue medication use at 12 and 24 weeks were extracted from these RCTs and analyzed using a NMA in a Bayesian framework.
Results
Data from 44 RCTs were included in the NMA. All FDCs showed improvements relative to placebo in terms of trough FEV
1
, SGRQ total score, and TDI focal score above clinically relevant thresholds, with the exception of TIO/olodaterol and aclidinium/formoterol, both of which failed to show clinically relevant improvements in SGRQ score at 24 weeks. All FDCs demonstrated reduced rescue medication use versus placebo. Open combinations demonstrated improved efficacy in all outcomes versus placebo, but these improvements did not consistently exceed clinically relevant thresholds for SGRQ and TDI scores. All once-daily FDCs showed improved efficacy versus TIO, but improvements were less consistently observed versus TIO with open dual combinations and combinations containing formoterol or salmeterol administered twice daily. Relative probabilities of improvement between FDCs highlighted potential between-class differences for trough FEV
1
but suggested little potential for differences in patient-reported outcomes.
Conclusion
LAMA + LABA combinations generally showed improved outcomes versus placebo and TIO. FDCs appeared to perform better than open dual combinations. A potential effectiveness gradient was observed between FDCs for objectively assessed functional outcomes, although further prospective trials are required to confirm these findings.
Funding
GSK.
Introduction
Appropriate timing for dual bronchodilator therapy initiation in chronic obstructive pulmonary disease (COPD) management is uncertain. Combination therapy is recommended as step-up from ...monotherapy or first-line treatment in patients with persistent symptoms. In this setting, umeclidinium/vilanterol (UMEC/VI) demonstrated improved lung function and reduced rescue medication use over tiotropium/olodaterol (TIO/OLO). This subgroup analysis explored efficacy differences between these combinations in patients naïve to COPD maintenance therapy before study entry.
Methods
Post hoc analysis of an 8-week, randomized, open-label, assessor-blind, two-period crossover study (204990; NCT02799784) comparing UMEC/VI 62.5/25 mcg and TIO/OLO 5/5 mcg, focused on maintenance-naïve (MN) patients with moderate COPD and persistent symptoms (modified Medical Research Council dyspnea score ≥ 2). Change from baseline (CFB) in trough forced expiratory volume in 1 s (FEV
1
), percentage of FEV
1
responders (CFB ≥ 100 ml), rescue medication use and safety were evaluated.
Results
The MN population comprised 63% of the intent-to-treat (ITT) population (148/236 patients) and had similar baseline demographics. At week 8, adjusted mean (standard error) improvements in trough FEV
1
from baseline were clinically meaningful for both combinations (UMEC/VI: 167 17 ml; TIO/OLO 110 18 ml; adjusted mean difference 95% confidence interval (CI): 57 23–92 ml;
p
= 0.001; %CFB: 11 vs. 8%). Proportion of FEV
1
responders was greater with UMEC/VI versus TIO/OLO at week 8 (60 vs. 42%; odds ratio 95% CI 1.90 1.12–3.22;
p
= 0.018). Reduction in rescue medication use was 0.20 (95% CI 0.07–0.34) puffs/day greater with UMEC/VI versus TIO/OLO over weeks 1–8 (
p
= 0.003). Adverse events incidence was similar (UMEC/VI: 24%; TIO/OLO: 29%).
Conclusions
These results highlight that the efficacy difference between UMEC/VI and TIO/OLO demonstrated in the ITT population is maintained in MN patients. Greater lung function improvements with UMEC/VI versus TIO/OLO were accompanied by symptom improvements, as reflected in a significantly lower need for supplemental rescue medication.
Funding
GSK.
Trial registration
NCT02799784
During asthma exacerbations, increased airway inflammation may impair the effects of beta(2)-adrenoceptor (beta(2)AR) agonists. It is unclear whether this impairment is prevented by inhaled ...glucocorticoids (GCs). We have investigated the relaxation of carbachol-contracted mouse tracheal segments to the beta(2)AR agonists formoterol, terbutaline, and salmeterol. The segments were pre-exposed for 4 days to the proinflammatory cytokines tumor necrosis factor alpha (100 ng/ml) and interleukin-1beta (10 ng/ml) with or without the GC, budesonide (1 microM). Formoterol and terbutaline induced greater maximal relaxation (R(max)) than salmeterol. The cytokines decreased R(max) of all beta(2)AR agonists, whereas budesonide had no effect. However, after concomitant treatment with cytokines and budesonide, the R(max) values of formoterol and terbutaline were not impaired, whereas budesonide did not prevent the decrease in the R(max) of salmeterol. A similar pattern was observed for cAMP production by the agonists. In tracheal smooth muscle, beta(2)AR mRNA was not affected by the cytokines but increased with budesonide. However, the cytokines markedly increased cyclooxygenase (COX)-2 mRNA expression, which may lead to heterologous desensitization of beta(2)AR. It is noteworthy that the cytokine-induced increase of COX-2 was blocked by concomitant budesonide suggesting that heterologous desensitization of beta(2)AR by the cytokines may be prevented by budesonide treatment. Budesonide prevented cytokine-induced impairment of the tracheal relaxation and beta(2)AR/cAMP signaling for formoterol but not for salmeterol. This suggests that differences exist between formoterol and salmeterol in beta(2)AR coupling/activation and/or signal transduction upstream of cAMP. These results imply that maximal bronchodilator effects of formoterol, but not of salmeterol, are maintained by budesonide treatment during periods with increased inflammation, such as asthma exacerbations.
Summary Budesonide/formoterol maintenance and reliever therapy (Symbicort SMART® ) reduces asthma exacerbations and symptoms versus fixed-dose regimens plus short-acting β2 -agonists (SABA) in ...double-blind trials. Information is lacking regarding its effectiveness versus conventional best practice (CBP). This pooled analysis of six 6-month, randomized, open-label studies examined asthma control and exacerbation risk in asthmatics (aged≥12 years). Patients ( N = 7855) symptomatic on inhaled corticosteroids (ICS) or stable/symptomatic on ICS/long-acting β2 -agonists (LABA) received budesonide/formoterol maintenance and reliever therapy (160/4.5 μg bid and as needed) or CBP (ICS or ICS/LABA ± other agents at an approved dose plus as-needed SABA). Overall asthma control was assessed comparing the incidence of exacerbations and levels of asthma control using the asthma control questionnaire (ACQ). Budesonide/formoterol maintenance and reliever therapy did not significantly reduce time to first severe exacerbation (primary variable) versus CBP ( P = 0.062). However, patients in this group experienced 15% fewer exacerbations (0.20 versus 0.24/patient/year; P = 0.021) and used 27% less ICS ( P < 0.0001). Odds of remaining well controlled (ACQ ≤0.75) over 6 months were higher with budesonide/formoterol maintenance and reliever therapy versus CBP (45% versus 41%, odds ratio OR 1.29; P < 0.01) while risk of remaining uncontrolled decreased (25% versus 29%, OR 0.81; P < 0.01). Budesonide/formoterol maintenance and reliever therapy improves key aspects of asthma control versus physicians' choice of CBP.
Introduction
Data on triple therapy (long-acting muscarinic antagonist LAMA + inhaled corticosteroid/long-acting beta
2
-agonist ICS/LABA) in symptomatic patients with chronic obstructive pulmonary ...disease (COPD) are limited. This post hoc analysis aimed to determine the efficacy of once-daily umeclidinium (UMEC; 62.5 μg) or placebo (PBO) plus open-label fixed-dose ICS/LABA in symptomatic patients with COPD.
Methods
Data were pooled from four randomized, double-blind, parallel-group trials (ClincalTrials.gov identifiers: NCT01772134, NCT01772147, NCT01957163, NCT02119286). Inclusion criteria included COPD diagnosis, modified Medical Research Council dyspnea scale score ≥2 and forced expiratory volume in 1 s (FEV
1
) <70% predicted. Following a 4-week run-in with once-daily or twice-daily ICS/LABA, patients were randomized to UMEC 62.5 μg or PBO as add-on therapy for 12 weeks. The efficacy of UMEC 62.5 μg + ICS/LABA or PBO + ICS/LABA in the intent-to-treat (ITT) population and subgroups with Global initiative for chronic Obstructive Lung Disease (GOLD) B and D COPD, and once-daily or twice-daily ICS/LABA was investigated. Outcomes included: trough FEV
1
, rescue-medication use, St George’s Respiratory Questionnaire (SGRQ) score, moderate/severe exacerbations. Adverse events (AEs) were assessed.
Results
UMEC 62.5 μg + ICS/LABA (ITT:
n
= 819) provided clinically important improvements in trough FEV
1
versus PBO + ICS/LABA ITT:
n
= 818; 130 mL (95% CI 112, 147);
P
< 0.001 at Day 85. Similar improvements occurred in all four subgroups (119–147 mL; all
P
< 0.001). In the ITT population, UMEC 62.5 μg + ICS/LABA decreased rescue-medication use, improved SGRQ score, and reduced short-term exacerbation risk (all
P
≤ 0.004 versus PBO + ICS/LABA). These three outcomes also improved consistently with UMEC 62.5 μg + ICS/LABA versus PBO + ICS/LABA with both ICS/LABAs and in the GOLD D subgroup. In the GOLD B subgroup a statistically significant benefit was observed in lung function and proportion of SGRQ responders. AE incidences were similar with UMEC 62.5 μg + ICS/LABA versus PBO + ICS/LABA.
Conclusion
In symptomatic patients with COPD, triple therapy with UMEC 62.5 μg + ICS/LABA improved lung function, reduced rescue-medication use, improved health-status and reduced exacerbation risk versus PBO + ICS/LABA, with similar safety profiles.
Funding
GSK (study number 202067).
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