Long-acting B-2 agonists (LABA) or long-acting muscarinic antagonists (LAMA): which one may be the first option in group A COPD patients?

INTRODUCTION: Long-acting muscarinic antagonists (LAMA) or beta-2 agonists (LABA) have been recommended for symptom control in group A COPD patients as a first-line bronchodilator treatment in GOLD guidelines. However, there is no mention of priority/superiority between the two treatment options. We aimed to compare the effectiveness of these treatments in this group. METHODS: The study cohort was formed of all subjects from six pulmonology clinics with an initial diagnosis of COPD who were new users of a LAMA or LABA from January 2020 to December 2021. Seventy-six group A COPD patients, in whom LABA or LAMA therapy had been started in the last 1 month as a first-line treatment, were included in our study. Participants were evaluated with spirometry, COPD Assessment Test (CAT), mMRC scale, and St. George Respiratory Questionnaire (SGRQ) for three times (baseline, 6-12th months). RESULTS: There were 76 group A COPD patients with LAMA (67.1%) and LABA (32.9%). The number of patients who improved in CAT score at the end of the first year was significantly higher in patients using LAMA than those using LABA (p = 0.022); the improvement at minimum clinically important difference (MCID) in CAT score of LAMA group at 1st year was also significant (p = 0.044). SGRQ total and impact scores were found to be statistically lower at 1st year compared to baseline in patients using LAMA (p = 0.010 and 0.006, respectively). Significant improvement was detected in CAT and SGRQ scores at the 6th month visit in the LAMA group having emphysema (p = 0.032 and 0.002, respectively). CONCLUSION: According to significant improvements in CAT and SGRQ score, LAMA may be preferred over LABA as a bronchodilator agent in group A COPD patients, especially in emphysema-dominant phenotype.

Single inhaler combination inhaled corticosteroid-formoterol as both maintenance and reliever (SMART) compared with a step up of treatment with fixed-dose inhaled corticosteroid-long-acting ß2-agonist maintenance with a short-acting ß2-agonist as reliever in adolescents and adults with poorly controlled asthma in Colombia: a cost-utility analysis.

OBJECTIVE: The aim of the present study was to determine the cost-utility of single inhaler combination inhaled corticosteroid and a long-acting ß2-agonist (ICS/LABAs) as both maintenance and reliever (SMART) compared with a step-up maintenance treatment with a fixed medium to high dose of ICS combined with LABA and a short-acting ß2-agonist (SABA) as reliever (ICS-LABA maintenance plus SABA) among patients aged 12 years or more with poorly controlled asthma in Colombia. METHODS: A Markov-type model was developed to estimate the costs and health outcomes of a simulated cohort of patients aged 12 years or more with uncontrolled asthma treated for 12 months. The main effectiveness data were obtained from a recent meta-analysis. The main outcome was the variable ''quality-adjusted life-years'' (QALYs). RESULTS: The base-case analysis showed that the budesonide/formoterol (BUD/FORM) SMART strategy was associated with lower overall treatment costs (US $3,062.37 vs. $4,462.02 average cost per patient over 12 months) and the greatest gain in QALYs (0.8511 vs. 0.8258 QALYs on average per patient over 12 months) compared with ICS-LABA maintenance plus SABA at step 4, thus leading to dominance. CONCLUSIONS: In patients aged 12 years or more with uncontrolled asthma at GINA step 3 or 4, the BUD/FORM SMART strategy at either step 3 or 4 is cost-effective compared with the ICS-LABA maintenance plus SABA at step 4 strategy, because it shows a greater gain in QALYs at lower total treatment costs.

Transcriptome analysis in patients with asthma after inhaled combination therapy with long-acting ß2-agonists and corticosteroids.

Introduction: Asthma is one of the major public health problems that imposes a great burden on societal, financial, and healthcare around the world. Asthma poorly affects the health-related quality of life and daily activities of patients. Treatment of asthma, including inhaled corticosteroids (ICS) and long-acting beta-agonists (LABAs), mainly aims to improve the lung function and reduce symptoms and exacerbations. Current treatment regimens are symptom-based strategies, and the status of airway inflammation after treatment is yet unknown. We conducted this study to understand the comprehensive inflammation or airway remodeling status of patients after ICS-LABA treatment through RNA transcriptome analysis. Materials and methods: Eight newly diagnosed asthmatic patients and two healthy subjects were recruited in this study. Asthmatic patients underwent blood tests, lung function test, and RNA transcriptome analysis before and after ICS-LABA treatment. Results: In comparison with healthy subjects, pretreatment asthmatic patients had higher expression of protein tyrosine kinase and related signaling pathways. After ICS-LABA treatment, the expression of nuclear receptor transcription coactivator, N-acetyltransferase, protein tyrosine kinase, nuclear receptor, and RNA polymerase II-activating transcription factor were downregulated. However, the post-treatment asthmatic patients still had higher expression of cysteine-type endopeptidase, endodeoxyribonuclease, apolipoprotein, and unfolded protein was still upregulated than healthy subjects. Conclusions: The combination of ICS/LABAs decreased airway inflammatory and remodeling pathways. However, allergen stimulation-related pathways were still upregulated in patients after ICS/LABA treatment. The combination of medication and allergen removal is a complete strategy for asthma.

Weight status and nonadherence to asthma maintenance therapy among children enrolled in a public drug insurance plan.

Objective: The pediatric obese-asthma phenotype is associated with poor control, perhaps because of medication nonadherence. This study aimed to assess whether weight status is associated with nonadherence in children prescribed new asthma maintenance therapies.Methods: A historical cohort was constructed from a clinical database linking individual patient and prescription data to Quebec's prescription claims registry. Children aged 2-18 years with specialist-diagnosed asthma who were newly prescribed one of the following maintenance controllers: leukotriene receptor antagonists (LTRA); low-dose inhaled corticosteroids (ICS); medium/high-dose ICS; or combination therapy (ICS with long-acting beta-2 agonists and/or LTRA), at the Asthma Center of the Montreal Children's Hospital from 2000-2007 were included. Primary nonadherence was defined as not claiming any prescriptions, whereas secondary nonadherence was measured with the proportion of prescribed days covered (PPDC ≤ 50%) among primary adherers over a 6-month follow-up period. A modified Poisson regression model served to estimate the effect of excess weight (BMI > 85th percentile) on primary and secondary nonadherence.Results: Approximately one third of patients were primary nonadherers and 60% took less than 50% of prescribed therapy. Excess weight was associated with a trend toward increased risk of primary nonadherence in children newly prescribed low-dose ICS (RR 1.53, 95%CI 0.94-2.49), and of secondary nonadherence in children initiating medium/high-dose ICS (RR 1.24; 95%CI 0.98-1.59).Conclusions: Excess weight status is a possible determinant of primary nonadherence in children initiating low-dose ICS and secondary nonadherence to higher-dose ICS regimens. This hypothesis-generating study suggests that nonadherence may be a potential contributor to higher morbidity in children with obese-asthma.

The pharmacokinetics, safety, and tolerability of single, high-strength doses of fluticasone propionate and fluticasone propionate/salmeterol delivered via a novel multidose dry powder inhaler in adolescents and adults with persistent asthma.

OBJECTIVE: Characterize fluticasone propionate (Fp) and combination fluticasone propionate and salmeterol (FS) pharmacokinetic and safety profiles, delivered via a novel, inhalation-driven, multidose dry powder inhaler (MDPI). METHODS: This multicenter, open-label, four-period crossover, single-dose study randomized patients aged ≥12 years with persistent asthma to Fp MDPI 200 mcg, FS MDPI 200/12.5 mcg, Fp dry powder inhaler (DPI) 500 mcg (250 mcg × 2 inhalations), or FS DPI 500/50 mcg. Blood samples for determination of Fp and salmeterol pharmacokinetic parameters including Cmax, AUC0-t, AUC0-inf, tmax, and t½ were collected predose through 36 h postdose (14 time points). Safety assessments comprised adverse events, vital signs, and physical examinations. The institutional review board approved the study protocol. RESULTS: The pharmacokinetic analysis set and safety population each included 40 patients. Fp systemic exposure (Cmax, AUC0-t, and AUC0-inf) was highest for Fp DPI 500 mcg and similar for Fp MDPI 200 mcg, FS MDPI 200/12.5 mcg, and FS DPI 500/50 mcg. Fp geometric mean t½ values were similar across treatments. Salmeterol Cmax was 20% lower and AUC0-t and AUC0-inf were approximately 50% lower with FS MDPI versus FS DPI. Median tmax and geometric mean t½ were similar between FS MDPI and FS DPI. Adverse events were similar across treatments with no relevant changes in vital signs, physical examinations, or hematology test results. CONCLUSIONS: Fp MDPI and FS MDPI produced similar or lower systemic exposure to Fp and salmeterol, despite lower doses, versus conventional DPI devices, suggesting improved efficiency due to formulation and device differences.

Randomized, double-blind trial evaluating the efficacy and safety of fluticasone propionate and fluticasone propionate/salmeterol delivered via multidose dry powder inhalers in patients with persistent asthma aged 12 years and older.

OBJECTIVE: To assess the efficacy and safety of fluticasone propionate (Fp) and Fp/salmeterol (FS) administered via a novel multidose dry powder inhaler (MDPI) that is easy to use correctly in asthma patients. METHODS: This phase-3, multicenter, double-blind, parallel-group study evaluated asthmatic patients (≥12 years of age) previously treated with either low- or mid-dose inhaled corticosteroids (ICSs) or ICS/long-acting beta agonists. After a 14- to 21-day run-in, patients were randomized to Fp MDPI 50 mcg, Fp MDPI 100 mcg, FS MDPI 50/12.5 mcg, FS MDPI 100/12.5 mcg, or placebo twice daily for 12 weeks. Change from baseline in forced expiratory volume in 1 second (FEV1; primary endpoint) was evaluated at week 12, and serial spirometry was collected at day 1 and week 12 (subset of patients). Safety was assessed by adverse events (AEs). RESULTS: The full analysis and serial spirometry subset included 640 and 312 patients, respectively. At week 12, FS MDPI significantly improved FEV1 from baseline at each dose vs corresponding Fp MDPI doses (p < 0.05). Change from baseline in FEV1 for active treatment groups was significantly greater vs placebo (p < 0.05). After 12 weeks, serial spirometry was significantly greater at all time points in the FS MDPI groups vs corresponding Fp MDPI groups (p < 0.05). Improvements in serial spirometry on day 1 were maintained through week 12. AEs were similar across groups. CONCLUSIONS: Pulmonary function was significantly improved with Fp MDPI and FS MDPI vs placebo and FS MDPI vs Fp MDPI. Active treatments had a safety profile comparable to placebo.

Fluticasone furoate/vilanterol once daily improves night-time awakenings in asthma patients with night symptoms: Post hoc analyses of three randomized controlled trials.

OBJECTIVE: Symptoms, including night-time awakenings, affect the quality of life of people with asthma. Fluticasone furoate/vilanterol (FF/VI) reduces exacerbations, improves lung function, and rescue-free and symptom-free 24-hour periods in patients with asthma. These post hoc analyses compared daytime and night-time symptoms in patients with asthma who received FF/VI, versus FF, fluticasone propionate (FP) or placebo. METHODS: Daytime and night-time symptoms were collected via electronic daily diary cards in three Phase III randomized studies of once-daily FF/VI in patients with uncontrolled asthma on inhaled corticosteroids (ICSs) ± long-acting beta2 agonists (n = 609/1039/586). Endpoints included change from baseline in symptom-free days and nights (analyzed by Analysis of Covariance, covariates: baseline, region, sex, age, and treatment), time for patients to achieve seven consecutive symptom-free nights (analyzed by Cox proportional hazards' model, covariates as above), and proportion of patients experiencing 100% symptom-free nights per week (analyzed by logistic regression, covariates: percentage of symptom-free nights, sex, age, and treatment). RESULTS: Improvements in symptom-free days and nights were generally observed for all treatments. More patients who received FF/VI experienced 100% symptom-free nights in the last week of the treatment period than patients who received ICS alone or placebo. FF/VI also reduced time to achieve seven consecutive symptom-free nights. Patients with at least one night of symptoms at baseline experienced an additional 2.7 and 2.0 symptom-free nights per week with FF/VI 100/25 µg, versus 1.9 and 1.7 with FF alone; similar findings were seen with FF/VI 200/25 µg. CONCLUSIONS: Benefits in terms of symptom-free days and nights were observed for patients receiving FF/VI versus comparators in these post hoc analyses.

LABA/LAMA Fixed Dose Combination in Chronic Obstructive Pulmonary Disease: The Impact on Health-Related Quality of Life.

BACKGROUND: While fixed dose combinations (FDCs) of long-acting beta 2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are increasingly tested on their efficacy in improving lung function, their effectiveness on Patient Reported Outcomes (PROs) such as Health Related Quality of Life (HRQoL) and Health Status (HS) deserve more attention. OBJECTIVES: To review current available evidence about the treatment effect of fixed LABA/LAMA FDCs on HRQoL. METHODS: A systematic literature search for randomized controlled trials (RCTs) about the impact of LABA/LAMA FDCs versus placebo, LABA or LAMA or LABA/ICS on HRQoL in Chronic obstructive pulmonary disease (COPD) patients has been performed. RESULTS: Twenty-eight RCTs (n = 32, 165 COPD patients) investigating the impact of fixed LABA/LAMA combinations on HRQoL were included. Using the St George' s Respiratory Questionnaire, 27 out of 28 trials assessed HRQoL. LABA/LAMA FDCs significantly improved HRQoL versus placebo in 9 out of 11 trials, while change when compared to other LABA or LAMA monocomponents was significantly better in 11 out 24. In 5 out of 6 RCTs having LABA/ICS as comparators, LABA/LAMA FDC had a similar effect and only 1 showed significant improvement in HRQL compared to LABA/ICS FDC. CONCLUSION: LABA/LAMA FDCs may be helpful in improving HRQoL, but because of the heterogeneity of performed trials, strong conclusions cannot be drawn. Moreover, due to the different molecule properties, treatment schedule, and device characteristics of each FDC, a generalized judgment seems inappropriate. Pragmatic trials powered to detect real-life differences in HRQoL and head-to-head comparison are needed to guide clinical practice in terms of PROs.

Formoterol and fluticasone propionate combination improves histone deacetylation and anti-inflammatory activities in bronchial epithelial cells exposed to cigarette smoke.

BACKGROUND: The addition of long-acting beta2-agonists (LABAs) to corticosteroids improves asthma control. Cigarette smoke exposure, increasing oxidative stress, may negatively affect corticosteroid responses. The anti-inflammatory effects of formoterol (FO) and fluticasone propionate (FP) in human bronchial epithelial cells exposed to cigarette smoke extracts (CSE) are unknown. AIMS: This study explored whether FP, alone and in combination with FO, in human bronchial epithelial cellline (16-HBE) and primary bronchial epithelial cells (NHBE), counteracted some CSE-mediated effects and in particular some of the molecular mechanisms of corticosteroid resistance. METHODS: 16-HBE and NHBE were stimulated with CSE, FP and FO alone or combined. HDAC3 and HDAC2 activity, nuclear translocation of GR and NF-κB, pERK1/2/tERK1/2 ratio, IL-8, TNF-α, IL-1ß mRNA expression, and mitochondrial ROS were evaluated. Actin reorganization in neutrophils was assessed by fluorescence microscopy using the phalloidin method. RESULTS: In 16-HBE, CSE decreased expression/activity of HDAC3, activity of HDAC2, nuclear translocation of GR and increased nuclear NF-κB expression, pERK 1/2/tERK1/2 ratio, and mRNA expression of inflammatory cytokines. In NHBE, CSE increased mRNA expression of inflammatory cytokines and supernatants from CSE exposed NHBE increased actin reorganization in neutrophils. FP combined with FO reverted all these phenomena in CSE stimulated 16-HBE cells as well as in NHBE cells. CONCLUSIONS: The present study provides compelling evidences that FP combined with FO may contribute to revert some processes related to steroid resistance induced by oxidative stress due to cigarette smoke exposure increasing the anti-inflammatory effects of FP.

A methodological comparison of two European primary care databases and replication in a US claims database: inhaled long-acting beta-2-agonists and the risk of acute myocardial infarction.

PURPOSE: Results from observational studies on inhaled long-acting beta-2-agonists (LABA) and acute myocardial infarction (AMI) risk are conflicting, presumably due to variation in methodology. We aimed to evaluate the impact of applying a common study protocol on consistency of results in three databases. METHODS: In the primary analysis, we included patients from two GP databases (Dutch-Mondriaan, UK-CPRD GOLD) with a diagnosis of asthma and/or COPD and at least one inhaled LABA or a "non-LABA inhaled bronchodilator medication" (short-acting beta-2-agonist or short-/long-acting muscarinic antagonist) prescription between 2002 and 2009. A claims database (USA-Clinformatics) was used for replication. LABA use was divided into current, recent (first 91 days following the end of a treatment episode), and past use (after more than 91 days following the end of a treatment episode). Adjusted hazard ratios (AMI-aHR) and 95 % confidence intervals (95 % CI) were estimated using time-dependent multivariable Cox regression models stratified by recorded diagnoses (asthma, COPD, or both asthma and COPD). RESULTS: For asthma or COPD patients, no statistically significant AMI-aHRs (age- and sex-adjusted) were found in the primary analysis. For patients with both diagnoses, a decreased AMI-aHR was found for current vs. recent LABA use in the CPRD GOLD (0.78; 95 % CI 0.68-0.90) and in Mondriaan (0.55; 95 % CI 0.28-1.08), too. The replication study yielded similar results. Adjusting for concomitant medication use and comorbidities, in addition to age and sex, had little impact on the results. CONCLUSIONS: By using a common protocol, we observed similar results in the primary analysis performed in two GP databases and in the replication study in a claims database. Regarding differences between databases, a common protocol facilitates interpreting results due to minimized methodological variations. However, results of multinational comparative observational studies might be affected by bias not fully addressed by a common protocol.

Effects of beclomethason/formoterol and budesonide/formoterol fixed combinations on lung function and airway inflammation in patients with mild to moderate asthma--an exploratory study.

RATIONALE: Asthma is a chronic inflammatory airway disease of the whole bronchial tree. In this exploratory study we investigated the effects of beclomethasone/formoterol (becl/form) and budesonide/formoterol (bud/form) fixed combinations on lung function and airway inflammation in patients with mild to moderate asthma. METHODS: 22 adult patients with asthma (mean FEV1 91.6% pred.) were recruited to this prospective phase IV, double-blind, double-dummy, two-way cross-over, single-centre, randomised study. After a 7 days run-in period with bud 200 µg bid patients were randomised to receive 4 weeks of becl/form (100/6 µg) bid in a pressurised metered dose inhaler or bud/form (160/4.5 µg) bid administered via dry powder inhaler. We measured spirometry, bodyplethysmography, impulse oscillometry, nitric oxide (NO) and its alveolar fraction (CAlv), and assessed sputum cellularity. RESULTS: CAlv significantly decreased after 4 weeks of treatment in each treatment period. The adjusted geometric mean (log transformed data, end of treatment vs. baseline) was 0.942 ppb (95% CI: 0.778-1.141 ppb) for becl/form and 0.903 ppb (95% CI: 0.741-1.099 ppb) for bud/form. Impulse oscillometry revealed a significant decrease in mean Delta R5-R20 of -0.033 kPa * L(-1) * sec(-1) for becl/form (95% CI: -0.064 to -0.002) and of -0.048 033 kPa * L(-1) * sec(-1) for bud/form (95% CI: -0.079 to -0.017). Other parameters of lung function and NO showed numerically small and in most cases statistically non-significant changes. CONCLUSIONS: In patients with mild to moderate asthma pre-treated with inhaled corticosteroids, the use of ICS/LABA formulations led to improvements of CAlv and Delta R5-R20 indicating that these parameters might be helpful to further assess the effects of inhaled ICS/LABA combinations on lung function and airway inflammation.

Comparing Costs and Healthcare Resource Utilization (HCRU) Using LAMA versus LABA/ICS at Treatment Initiation for COPD: Findings from CITRUS (Comparing the Incidence of Tiotropium and ICS/LABA in Real-World Use in South Korea) Study.

Background: COPD causes substantial economic burden on healthcare. Alternative treatment strategies for COPD can be associated with different costs dependent upon their relative safety and effectiveness. We compared costs and healthcare resource utilization (HCRU) associated with LAMA or LABA/ICS initiation. Methods: Using the Korean National Health Insurance Service database, we enrolled COPD patients initiating treatment with LAMA or LABA/ICS between January 2005 and April 2015. Propensity score matched individuals were compared on all-cause and COPD-related medical costs and HCRU over a three-year follow-up period. Results: A total of 2444 patients were enrolled in each treatment group. LAMA group was associated with significantly lower costs than LABA/ICS group, both in all-cause (403.08 vs 474.50 USD per patient per month [PPPM], cost ratio 1.18, 95% confidence interval [CI]=1.10-1.26, p<0.0001) and COPD-related (216.37 vs 267.32 USD PPPM, cost ratio 1.24, 95% CI=1.13-1.35, p<0.0001) medical costs. All-cause HCRU was not significantly different between groups, while COPD-related HRCU was higher in LAMA group (0.66 vs 0.60 medical visits PPPM, p<0.0001). Conclusion: COPD patients initiating treatment with LAMA were associated with lower all-cause and COPD-related medical costs than those starting with LABA/ICS despite the similar all-cause HCRU and higher COPD-related HCRU. Initiation with LAMA is a cost-efficient option for the treatment of COPD.

Prescribing Patterns for Long-Acting Inhaled Bronchodilators Among Rural Adults With Chronic Obstructive Pulmonary Disease.

Background: Chronic obstructive pulmonary disease (COPD) is prevalent in rural areas of the USA. Long-acting inhaled bronchodilators (LABDs) are a key tool in COPD management and are underutilized. The purpose of this study was to determine whether rates of prescriptions for LABD differed by payer among patients with COPD in a rural healthcare network. Methods: In analysis 1, a random sample of patients with spirometry- and symptom-confirmed COPD over April 1, 2017 to December 31, 2019 was identified. Patient characteristics, including payer status, extracted from medical records were compared for those who did and did not have any prescriptions for LABD during the study window. In analysis 2, patients with one or more COPD-related hospitalizations during the same time period were identified and similar comparisons were made by LABD prescription status. Results: Among a random sample of patients with spirometry-confirmed COPD, 93.0% had been prescribed LABD during the study window with no difference in proportion by payer. Among the 461 patients with a COPD-related hospitalization, 388 (84.2%) had been prescribed LABD, again with no difference in prescriptions by payer. Those with a COPD-related hospitalization who had been prescribed LABD were younger, had lower body mass index, were more likely to be current smokers and had higher rates of hospitalizations for COPD during the study period than those not prescribed LABD. Conclusion: While disparities in LABD utilization may occur due to cost or other barriers to filling prescriptions, in our study, prescriptions for LABD were common and did not differ by payer status.

Long-term real-world effectiveness of allergy immunotherapy in patients with allergic rhinitis and asthma: Results from the REACT study, a retrospective cohort study.

BACKGROUND: Allergen immunotherapy (AIT) is the only causal treatment for respiratory allergy. Long-term real-life effectiveness of AIT remains to be demonstrated beyond the evidence from randomised controlled trials (RCTs). METHODS: REACT (Real world effectiveness in allergy immunotherapy) is a retrospective cohort study using claims data between 2007 and 2017. Study eligibility was a confirmed diagnosis of allergic rhinitis (AR), with or without asthma, and AIT. To ensure comparable groups, AIT-treated subjects were propensity score matched 1:1 with control subjects, using characteristic and potential confounding variables. Outcomes were analysed as within (pre vs post AIT) and between (AIT vs control) group differences across 9 years of follow-up (ClinicalTrial.gov: NCT04125888). FINDINGS: 46,024 AIT-treated subjects were matched with control subjects and 14,614 were included in the pre-existing asthma cohort. AIT-treated subjects were 29·5 (16·3) years and 53% were male. Compared to pre-index year, AIT was consistently associated with greater reductions compared to control subjects in AR and asthma prescriptions, including both asthma controller and reliever prescriptions. Additionally, the AIT group had significantly greater likelihood of stepping down asthma treatment (P <0·0001). In addition to the reduction in asthma treatment in the AIT group, a greater reduction in severe asthma exacerbations was demonstrated (P<0·05). Reductions in pneumonia with antibiotic prescriptions, hospitalisations, and duration of inpatients stays were all in favour of AIT. INTERPRETATION: The study extends the existing RCT evidence for AIT by demonstrating longer-term and sustained effectiveness of AIT in the real world. Additionally, in patients with concurrent asthma, AIT was associated with reduced likelihood of asthma exacerbations and pneumonia. FUNDING: The study was funded by ALK A/S.

Cardiovascular safety of mometasone/indacaterol and mometasone/indacaterol/glycopyrronium once-daily fixed-dose combinations in asthma: pooled analysis of phase 3 trials.

OBJECTIVE: To evaluate cardiovascular safety of two new inhaled fixed-dose combinations for treatment of asthma: (i) the inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) mometasone furoate/indacaterol acetate (MF/IND), (ii) the ICS/LABA/long-acting muscarinic antagonist (LAMA) MF/IND/glycopyrronium bromide (GLY). METHODS: Patient-level data were pooled from four randomized trials, including 52-week studies PALLADIUM (n = 2216) and IRIDIUM (n = 3092), 24-week study ARGON (n = 1426), and 12-week study QUARTZ (n = 802). Cardio-/cerebrovascular (CCV) event frequencies were examined in the following comparisons: (1) LABA effect: pooled-dose MF/IND vs. pooled-dose MF; (2) LAMA effect: pooled-dose MF/IND/GLY vs. pooled-dose MF/IND; (3) ICS-dose effects: (a) high-dose MF/IND vs. medium-dose MF/IND, (b) high-dose MF/IND/GLY vs. medium-dose MF/IND/GLY; (4) intra-class effects: (a) high-dose MF/IND vs. Fluticasone/Salmeterol (F/S), (b) high-dose MF/IND/GLY vs. F/S + Tiotropium (TIO). Risk estimates (percentage of patients with ≥1 CCV event) and risk differences (RDs) with 95% confidence intervals (CIs) were calculated for each comparison. RESULTS: The frequency of CCV events was low, without notable differences between comparison groups. Risk estimates and corresponding RDs (95% CIs) were as follows: (1) pooled-dose MF/IND = 2.35%, pooled-dose MF = 2.18%, RD = 0.17% (-1.00%, 1.34%); (2) pooled-dose MF/IND/GLY = 3.65%, pooled-dose MF/IND = 3.77%, RD = -0.12% (-1.63%, 1.39%); (3a) high-dose MF/IND = 3.69%, medium-dose MF/IND = 3.35%, RD = 0.34% (-1.25%, 1.94%); (3b) high-dose MF/IND/GLY = 2.84%, medium-dose MF/IND/GLY = 2.02%, RD = 0.82% (-0.49%, 2.13%); (4a) high-dose MF/IND = 3.69%, F/S = 2.82%, RD = 0.87% (-0.66%, 2.40%); (4b) high-dose MF/IND/GLY = 1.26%, F/S + TIO = 1.05%, RD = 0.21% (-1.26%, 1.68%). CONCLUSIONS: There was no evidence of increased cardiovascular risk attributable to the addition of IND to MF or addition of GLY to MF/IND. Similarly, no evidence of increased cardiovascular risk was observed with an increase in the ICS-dose or relative to F/S ± TIO.

Effectiveness and safety of a glutaraldehyde-modified, L-tyrosine-adsorbed and monophosphoryl lipid A-Adjuvanted allergen immunotherapy in patients with allergic asthma sensitized to olive pollen: A retrospective, controlled real-world study.

BACKGROUND: Allergy to olive pollen is one of the primary causes of allergic asthma in Spain. Even though allergen immunotherapy (AIT) has shown clinical benefits in patients sensitized to different allergens, studies in asthmatic patients sensitized to olive pollen are insufficient. OBJECTIVE: To assess the effectiveness and safety of an ultra-short course of AIT with an L-tyrosine-adsorbed and monophosphoryl lipid A-adjuvanted olive pollen and olive/grass pollen extract (Pollinex Quattro®) in patients with allergic asthma in the real-world setting. METHODS: Retrospective, controlled study including patients with asthma, with and without allergic rhinitis, caused by sensitization to olive pollen from 11 centers in Spain. Patients received out-of-season (October-March) treatment with AIT in addition to their pharmacological treatment (active group) or pharmacological treatment (control group). Effectiveness variables, including unscheduled visits to the healthcare center, emergency room admissions, symptoms of asthma and rhinitis (following GEMA and ARIA classifications, respectively), and use of medication to treat asthma and rhinitis during the subsequent pollen season were compared between treatment groups. RESULTS: Of 131 study patients, 42 were treated with their usual asthma medication (control group) and 89 were treated with AIT (active group), either Pollinex Quattro® 100% olive pollen (n = 43, 48.3%) or 50% olive pollen/50% grass pollen (n = 46, 51.7%). Patients' demographic and clinical characteristics were similar between groups. The mean (SD) number of unscheduled visits to a healthcare center and emergency room admissions due to allergy symptoms was 2.19 (1.40) and 0.43 (0.63) in the control group, and 1.09 (1.25) and 0.11 (0.51) in the active group (P = 0.001 and P = 0.006, respectively). Severity and control of asthma symptoms remained unchanged (P = 0.347 and P = 0.179, respectively), rhinitis type improved (P = 0.025), and severity remained unchanged in the active compared to the control group. The use of short-acting beta-agonists and inhaled corticosteroids to treat asthma symptoms decreased in the active vs. the control group (P = 0.001 and P = 0.031, respectively). Twelve (13.5%) and two (2.2%) patients in the active group experienced local adverse reactions (edema, swelling, erythema, hives, pruritus, and heat), and systemic adverse reactions (hypertensive crisis and low-grade fever) to AIT, respectively; none was serious. CONCLUSION: AIT with Pollinex Quattro® specific for olive pollen and olive/grass pollens resulted in reduced visits to the healthcare center and emergency room and the use of asthma medication during the pollen season, indicating that this treatment was safe and effective in treating asthma in patients sensitized to these pollens.

Long-term safety and efficacy of formoterol fumarate inhalation solution in patients with moderate-to-severe COPD.

BACKGROUND: Formoterol fumarate inhalation solution (FFIS; Perforomist®) is a long-acting ß2-agonist (LABA) marketed in the US as a nebulized COPD maintenance treatment. Because long-term LABA use was associated with a potential increased risk of exacerbation or death in asthma patients, the US Food and Drug Administration (FDA) requested a postmarketing commitment study to evaluate long-term safety in COPD patients. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, noninferiority study. Patients (N=1,071; mean age, 62.6 years; 48.5% male; 89.7% white) with moderate-to-severe COPD on stable COPD therapy received FFIS (20 µg; n=541) or placebo (n=530) twice daily. The primary end point was the combined incidence of respiratory death, first COPD-related ER visit, or first COPD exacerbation-related hospitalization during 1 year post randomization. Noninferiority to placebo was concluded if the two-sided 90% CI of the HR of FFIS to placebo was <1.5. Secondary end points included spirometry. RESULTS: The planned 1-year treatment period was completed by 520 patients; 551 discontinued prematurely (FFIS: 45.7%; placebo: 57.4%). The median treatment duration was approximately 10 and 7 months for FFIS and placebo, respectively. Among 1,071 randomized patients, 121 had ≥1 primary event (FFIS: 11.8%; placebo: 10.8%). The estimated HR of a primary event with FFIS vs placebo was 0.965 (90% CI: 0.711, 1.308), demonstrating that FFIS was noninferior to placebo. No respiratory deaths were observed in the FFIS group. Adverse events were similar for FFIS vs placebo (patients with ≥1 treatment-emergent adverse events: 374 [69.1%] vs 369 [69.6%], respectively). Compared with placebo, FFIS demonstrated statistically greater improvements from baseline in trough FEV1, FVC, percent predicted FEV1, and patient-reported outcomes (Transition Dyspnea Index). CONCLUSIONS: Nebulized FFIS was noninferior to placebo with respect to safety in patients with moderate-to-severe COPD. Additionally, fewer treatment withdrawals and larger lung function improvements were observed with FFIS compared with placebo when added to other maintenance COPD therapies.

Medication management patterns among Medicare beneficiaries with chronic obstructive pulmonary disease who initiate nebulized arformoterol treatment.

Purpose: Global evidence-based treatment strategies for chronic obstructive pulmonary disease (COPD) recommend using long-acting bronchodilators (LABDs) as maintenance therapy. However, COPD patients are often undertreated. We examined COPD treatment patterns among Medicare beneficiaries who initiated arformoterol tartrate, a nebulized long-acting beta2 agonist (LABA), and identified the predictors of initiation. Methods: Using a 100% sample of Medicare administrative data, we identified beneficiaries with a COPD diagnosis (ICD-9 490-492.xx, 494.xx, 496.xx) between 2010 and 2014 who had ≥1 year of continuous enrollment in Parts A, B, and D, and ≥2 COPD-related outpatient visits within 30 days or ≥1 hospitalization(s). After applying inclusion/exclusion criteria, three cohorts were identified: (1) study group beneficiaries who received nebulized arformoterol (n=11,886), (2) a subset of the study group with no LABD use 90 days prior to initiating arformoterol (n=5,542), and (3) control group beneficiaries with no nebulized LABA use (n=220,429). Logistic regression was used to evaluate predictors of arformoterol initiation. Odds ratios (ORs), 95% confidence intervals (CIs), and p values were computed. Results: Among arformoterol users, 47% (n=5,542) had received no LABDs 90 days prior to initiating arformoterol. These beneficiaries were being treated with a nebulized (50%) or inhaled (37%) short-acting bronchodilator or a systemic corticosteroid (46%), and many received antibiotics (37%). Compared to controls, beneficiaries who initiated arformoterol were significantly more likely to have had an exacerbation, a COPD-related hospitalization, and a pulmonologist or respiratory therapist visit prior to initiation (all p<0.05). Beneficiaries with moderate/severe psychiatric comorbidity or dual-eligible status were significantly less likely to initiate arformoterol, as compared to controls (all p<0.05). Conclusion: Medicare beneficiaries who initiated nebulized arformoterol therapy had more exacerbations and hospitalizations than controls 90 days prior to initiation. Findings revealed inadequate use of maintenance medications, suggesting a lack of compliance with evidence-based treatment guidelines.

Risk of sepsis among patients with COPD treated with fixed combinations of inhaled corticosteroids and long-acting Beta2 agonists.

This study aimed to compare the effect of budesonide/formoterol and fluticasone/salmeterol on the risk and outcomes of sepsis in COPD patients. We conducted this study using the Taiwan National Health Insurance Research Database. We included COPD patients prescribed with budesonide/formoterol or fluticasone/salmeterol between 2004 and 2011. Outcomes including sepsis and mortality were measured. 10,267 COPD patients who received fluticasone/salmeterol and 6,844 patients who received budesonide/formoterol were enrolled into this study and then subsequence were adjusted by propensity score weighting. The incidence of sepsis was 5.74 and 4.99 per 100 person-years for the patients receiving fluticasone/salmeterol and budesonide/formoterol, respectively. Fluticasone/salmeterol was associated with higher risk of sepsis (aHR, 1.15; 95%CI, 1.07-1.24) and septic shock (aHR, 1.14; 95%CI, 1.01-1.29) than budesonide/formoterol. Besides, fluticasone/salmeterol was associated with higher risk of death (aHR, 1.090; 95%CI, 1.01-1.18) than budesonide/formoterol. Patients receiving fluticasone/salmeterol had a significant higher risk of sepsis related respiratory organ dysfunction, lower respiratory tract infection, genitourinary tract infection, bacteremia and skin infection. In conclusion, long-term treatment with budesonide/formoterol was associated with lower rates of sepsis and deaths than fluticasone/salmeterol in patients with COPD.

Reduction in Hospital Readmission Rates Among Medicare Beneficiaries With Chronic Obstructive Pulmonary Disease: A Real-world Outcomes Study of Nebulized Bronchodilators.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is a common condition responsible for substantial morbidity, mortality, and costs in the United States. The economic burden of COPD is driven primarily by hospitalizations, with 1 in 5 hospitalized patients experiencing a 30-day readmission. Bronchodilators, delivered via handheld inhalers or nebulizers, are the mainstay of therapy for COPD. However, differences in outcomes between short- and long-acting therapies are unclear. We examined real-world differences in 30-day readmission and exacerbation rates between Medicare beneficiaries with COPD treated with a nebulized long-acting beta2-agonist (arformoterol tartrate [ARF]) and beneficiaries treated with a nebulized short-acting beta2-agonist (SABA) for maintenance therapy after hospital discharge. METHODS: Truven MarketScan Hospital Drug Database and Medicare files were probabilistically matched between 2009 and 2013 to identify beneficiaries who were aged ≥65 years and discharged from a hospital with a primary COPD diagnosis or a secondary COPD diagnosis and a primary diagnosis for another respiratory condition. Matching was performed by using COPD hospitalization date (±7 days) and source, length of stay (±1 day), discharge date and destination, and hospital region. After applying additional inclusion/exclusion criteria, 2 cohorts were created: nebulized ARF users (n = 953) and nebulized SABA users (n = 6939). Logistic regression analyses were used to examine 30-day readmission (all-cause and COPD related) and exacerbation rates. Odds ratios (ORs), 95% CIs, and P values were computed. FINDINGS: On average, nebulized SABA users had more comorbidities than nebulized ARF users, including diabetes, atrial fibrillation, renal disease, musculoskeletal disease, myocardial infarction, and cognitive impairment (all, P < 0.0001). However, nebulized ARF users had a higher average COPD severity score than nebulized SABA users (49.5 v. 38.0; P < 0.001). COPD therapies at baseline were similar in both cohorts and included systemic corticosteroids (≥65%), short-acting bronchodilators (≥33%), and inhaled corticosteroids + long-acting beta2-agonists (30%). After adjusting for sociodemographic and hospital characteristics, concomitant medications, and case-mix, nebulized ARF users had 27% lower odds of an all-cause readmission (OR, 0.73; 95% CI, 0.59-0.92; P = 0.008) and 23% lower odds of a COPD-related readmission (OR, 0.77; 95% CI, 0.60-0.98; P = 0.032) at 30 days compared with users of a nebulized SABA. No difference was found in 30-day exacerbation rates between the cohorts. IMPLICATIONS: Nebulized ARF users had lower 30-day readmission rates, greater COPD severity, and fewer comorbidities than nebulized SABA users. In this population, maintenance treatment with ARF reduced costly COPD outcomes.