Salbutamol Easyhaler provides non-inferior relief of methacholine induced bronchoconstriction in comparison to Ventoline Evohaler with spacer: A randomized trial.

BACKGROUND: Salbutamol is a cornerstone for relieving acute asthma symptoms, typically administered through a pressurized metered-dose inhaler (pMDI). Dry powder inhalers (DPIs) offer an alternative, but concerns exist whether DPIs provide an effective relief during an obstructive event. OBJECTIVE: We aimed to show non-inferiority of Salbutamol Easyhaler DPI compared to pMDI with spacer in treating methacholine-induced bronchoconstriction. Applicability of Budesonide-formoterol Easyhaler DPI as a reliever was also assessed. METHODS: This was a randomized, parallel-group trial in subjects sent to methacholine challenge (MC) test for asthma diagnostics. Participants with at least 20 % decrease in forced expiratory volume in 1 s (FEV1) were randomized to receive Salbutamol Easyhaler (2 × 200 µg), Ventoline Evohaler with spacer (4 × 100 µg) or Budesonide-formoterol Easyhaler (2 × 160/4.5 µg) as a reliever. The treatment was repeated if FEV1 did not recover to at least -10 % of baseline. RESULTS: 180 participants (69 % females, mean age 46 yrs [range 18-80], FEV1%pred 89.5 [62-142] %) completed the trial. Salbutamol Easyhaler was non-inferior to pMDI with spacer in acute relief of bronchoconstriction showing a -0.083 (95 % LCL -0.146) L FEV1 difference after the first dose and -0.032 (-0.071) L after the last dose. The differences in FEV1 between Budesonide-formoterol Easyhaler and Salbutamol pMDI with spacer were -0.163 (-0.225) L after the first and -0.092 (-0.131) L after the last dose. CONCLUSION: The study confirms non-inferiority of Salbutamol Easyhaler to Ventoline Evohaler with spacer in relieving acute bronchoconstriction, making Easyhaler a sustainable and safe reliever for MC test and supports its use during asthma attacks.

Budesonide/Glycopyrrolate/Formoterol for the Management of COPD in a UK Primary Care Population: Real-World Use and Early Medication Success.

Purpose: Real-life research is needed to evaluate the effectiveness of budesonide/glycopyrrolate/formoterol (BGF) in routine COPD primary care management. We assessed the frequency of medication success among patients with COPD who initiated BGF using real-world data. Patients and Methods: Patients with a recorded diagnostic COPD code who started BGF with ≥2 prescriptions within 90-days were identified in the UK Optimum Patient Care Research Database and followed from first prescription until censoring at the end of follow-up (180-days), death, leaving database or end of data at 24/10/2022. The primary outcome was medication success at 90-days post-BGF initiation, defined as no major cardiac or respiratory event (ie no complicated COPD exacerbation, hospitalization for any respiratory event, myocardial infarction, new/hospitalized heart failure, and death) and no incidence of pneumonia. Medication success was also assessed at 180-days post-BGF initiation. Overall real-life medication success was claimed if the lower 95% confidence interval (CI) for the proportion of patients meeting the primary outcome was ≥70% (defined a priori). Results: Two hundred eighty-five patients were included. Prior to BGF initiation, these patients often had severe airflow obstruction (mean ppFEV1: 54.5%), were highly symptomatic (mMRC ≥2: 77.9% (n = 205/263); mean CAT score: 21.7 (SD 7.8)), with evidence of short-acting ß2-agonist (SABA) over-use (≥3 inhalers/year: 62.1%, n=179/285), repeat OCS prescriptions (≥2 courses/year: 33.0%, n = 95/285) and multiple primary care consultations (≥2 visits/year: 61.1%, n = 174/285). Overall, 39.6% of patients (n = 113/285) switched from previous triple therapies. Real-life medication success was achieved by 96.5% of patients (n = 275/285 [95% CI: 93.6, 98.3]) during 90-days treatment with BGF and by 91.8% (n = 169/184 [95% CI: 86.9, 95.4]) of patients at 180-days. The prescribed daily dose of SABA remained stable over the study period. Conclusion: The majority of patients initiating BGF experienced real-life medication success reflecting the absence of severe cardiopulmonary events. These benefits were apparent after 90-days of treatment and sustained over 180-days.

Optimal Inhalation Flow Pattern from Turbuhaler Predicted by Laser Photometry.

Background: The emitted dose (ED) from most dry powder inhalers (DPIs) is almost independent of peak inspiratory flow (PIF) above a certain value, which is specific to the individual DPI. However, the ED of the Turbuhaler® (TBH) increases linearly with PIF increments. This study investigated the powder clearance and clinical utility of TBH performance features by using the photo-reflection method (PRM), a type of laser photometry. Methods: Pulmicort® (PLM) (containing budesonide only) and Symbicort® (SMB) (drugs with lactose particles) were inspired with a ramp-up pattern of several PIF intensities using a vacuum pump. Time trajectories of particle release and PIF were then compared. Results: The particle-release trajectories from both types of DPIs were similar, consisting of a sharp increment phase (∼0.15 seconds) followed by exponential decay. Both onset to the peak of particle-release time and particle-release times were not affected by PIF changes when the PIF was >40 L/min. EDs from both TBHs were linearly related to PIFs, and the slope of the regression equation for SMB was 2.4-fold larger than that of PLM. The peak of the released particles (PKIED) was also linearly related to PIF. A linear relationship was also observed between ED and PKIED in both TBHs, and these regression lines overlapped. Conclusion: EDs from the TBH were dependent on PKIED. Therefore, rapid, initially strong, and deep inhalation should be advised while using the TBH. PRM could measure the fine and small amount of particles released from the TBH.

Comparing initial LABA-ICS inhalers in COPD: Real-world effectiveness and safety.

BACKGROUND: Guidelines for the treatment of chronic obstructive pulmonary disease (COPD) patients with multiple exacerbations and eosinophilia recommend a long-acting beta2-agonist (LABA) and inhaled corticosteroid (ICS) combined inhaler, with no distinction between different agents. We compared the effectiveness and safety of budesonide-formoterol versus fluticasone-salmeterol on the incidence of exacerbations and pneumonia in a real-world clinical practice setting of COPD, particularly considering eosinophilia, an important marker for ICS effectiveness. METHODS: We identified a cohort of patients with COPD, new users of a LABA-ICS during 2002-2018, age 50 or older, from the UK's CPRD database, and followed for one year. The hazard ratio (HR) of exacerbation and of pneumonia was estimated using the Cox regression model, weighted by fine stratification of the propensity score of treatment initiation. RESULTS: The cohort included 24,973 of budesonide-formoterol and 61,251 initiators of fluticasone-salmeterol. The adjusted HR of a first moderate or severe exacerbation with budesonide-formoterol relative to fluticasone-salmeterol was 0.98 (95% CI: 0.95-1.01), while for severe exacerbation it was 0.92 (95% CI: 0.85-0.99). The HR of severe pneumonia with budesonide-formoterol was 0.76 (95% CI: 0.70-0.83), and was particularly decreased with higher blood eosinophil count, dropping to 0.62 (95% CI: 0.51-0.77) at >300 cells/µL. CONCLUSION: In a real-world clinical setting of COPD treatment, a budesonide-formoterol inhaler was generally as effective at reducing the incidence of moderate-severe exacerbations as fluticasone-salmeterol. However, budesonide-formoterol was more effective than fluticasone-salmeterol at reducing the incidence of severe exacerbation and the risk of severe pneumonia, particularly in patients with higher blood eosinophil counts.

Incorrect Holding Angle of Dry Powder Inhaler during the Drug-Loading Step Significantly Decreases Output Efficiency.

It is well known that correct use of inhalers plays a critical role in optimal inhalation therapy, but the impact of incorrect inhaler use on pulmonary drug delivery has not been quantitatively evaluated. The aim of this study was to investigate the frequency of holding inhalers at incorrect angles during the drug-loading step while using Turbuhaler® and to quantify the influence of the inhaler angle on in vitro pulmonary delivery. Thirty patients prescribed Turbuhaler® at Shiga University of Medical Science Hospital were enrolled. During inhalation, the participants' inhalation techniques were assessed by clinical pharmacists. Additionally, the influence of the inhaler angle on pulmonary delivery of budesonide via Symbicort® Turbuhaler® was investigated using a Twin-Stage Liquid Impinger. Output efficiency (OE), stage 2 deposition (St2), and OE × St2 were calculated. An incorrect angle during the drug-loading step was observed in 33.3% of the participants. In vitro testing demonstrated that OE, an index of the loaded dose, significantly decreased by 73.3% at an incorrect angle, while St2, an index of the deagglomerating efficiency, was stable independent of the holding angle. OE × St2, indicating the bronchial and pulmonary drug delivery amount, decreased by 76.9%. An incorrect holding angle reduced the loaded dose, resulting in decreased pulmonary delivery. Error in the inhaler angle occurs frequently and demonstrates a considerable impact on pulmonary drug delivery. Hence, it is necessary to assess the Turbuhaler® angle during inhalation.

Patient experiences of as-needed budesonide-formoterol by Turbuhaler® for treatment of mild asthma; a qualitative study.

BACKGROUND: Combination low-dose budesonide-formoterol, taken as-needed for symptom relief reduces exacerbation risk and is recommended for treatment of mild asthma. The NovelQ qualitative study explored patients' attitudes toward using this novel therapy. METHODS: Adults with mild asthma using reliever-only treatment were randomised to as-needed budesonide-formoterol Turbuhaler® in a multinational, 52-week open-label randomised controlled trial (NovelSTART-ACTRN12615000999538). A subgroup were interviewed to explore their attitudes to use of as-needed budesonide-formoterol after receiving it for ≥10 months. Semi-structured interviews were conducted until saturation, audio-recorded, and thematically analysed. RESULTS: Analysis of 35 participants (66% female; mean age 43.5 [range 18-74]; mean Asthma Control Questionnaire score 1.09 ± SD0.55) interviews identified 5 themes, each including both barriers and facilitators to therapy use. Themes were: 'Treatment effectiveness' i.e. how well symptoms were relieved and/or prevented; 'Lifestyle fit of the regimen' e.g. the extent to which the treatment regimen integrated into the patient's daily life; 'Attitudes toward medication use and safety' e.g. openness for new reliever treatments, beliefs about treatment necessity or side effects; 'Device attributes' e.g. perceived ease of use; and 'Doctor-patient relationship' e.g. impact of health professional support on new treatment acceptance. CONCLUSIONS: A wide range of factors seem to drive the opinions of mild asthma patients on as-needed budesonide-formoterol therapy. Many patients perceived both positive and negative treatment attributes, and their individual evaluation of these attributes determined their likelihood of using it after the study. Supportive patient-physician interactions appear key to addressing patient barriers. Recommendations for patient-centred discussions, developed from this research, are provided.

Combination budesonide/formoterol inhaler as sole reliever therapy in Maori and Pacific people with mild and moderate asthma.

AIM: In the PRACTICAL study, as-needed budesonide/formoterol reduced the rate of severe exacerbations compared with maintenance budesonide plus as-needed terbutaline. In a pre-specified analysis we analysed the efficacy in Maori and Pacific peoples, populations with worse asthma outcomes. METHOD: The PRACTICAL study was a 52-week, open-label, parallel group, randomised controlled trial of 890 adults with mild to moderate asthma, who were randomised to budesonide/formoterol Turbuhaler 200/6mcg one actuation as required or budesonide Turbuhaler 200mcg one actuation twice daily and terbutaline Turbuhaler 250mcg two actuations as required. The primary outcome was rate of severe exacerbations. The analysis strategy was to test an ethnicity-treatment interaction term for each outcome variable. RESULTS: Seventy-two participants (8%) identified as Maori, 36 participants (4%) as Pacific ethnicity. There was no evidence that ethnicity was an effect modifier for severe exacerbations (P interaction 0.70). CONCLUSION: The reduction in severe exacerbation risk with budesonide-formoterol reliever compared with maintenance budesonide was similar in Maori and Pacific adults compared with New Zealand European/Other.

The cost-effectiveness of as-needed budesonide/formoterol versus low-dose inhaled corticosteroid maintenance therapy in patients with mild asthma in the UK.

BACKGROUND: As-needed budesonide/formoterol is effective in patients with mild asthma for whom low-dose inhaled corticosteroid (ICS) maintenance therapy is appropriate. We assessed the cost-effectiveness of this regimen versus maintenance low-dose ICS plus as-needed short-acting ß2-agonist (SABA). METHODS: A probabilistic Markov cohort model was developed that simulated time within/outside severe asthma exacerbations, conducted from a UK NHS perspective with a 70-year time horizon. Clinical efficacy inputs were derived from the SYGMA 2 trial. Patients with mild asthma eligible for low-dose maintenance ICS therapy received as-needed budesonide/formoterol 200/6 µg or twice-daily budesonide 200 µg maintenance therapy plus as-needed terbutaline 0.5 mg. A severe exacerbation was defined as worsening asthma requiring systemic corticosteroid use alone/in combination with an emergency department visit, or hospitalisation for acute asthma. Utility values were derived from SYGMA 2 EQ-5D-5L data, and all-cause- and asthma-related mortality, reduction in utility of an exacerbation, and costs were based on published data. The base-case analysis discount rate was 3.5%. Model robustness was evaluated with one-way sensitivity, probabilistic sensitivity, and two scenario analyses. RESULTS: On average, as-needed budesonide/formoterol was associated with a £292.99 cost saving and quality-adjusted life year (QALY) gains of 0.001 versus ICS + SABA. At a willingness-to-pay of £20,000/QALY, as-needed budesonide/formoterol had >85% probability of being cost-effective versus ICS + SABA. Key drivers were budesonide/formoterol and budesonide maintenance annual exacerbation rates, mean daily budesonide/formoterol inhalations, and costs and outcomes discount rates. CONCLUSIONS: From a UK healthcare payer perspective, as-needed budesonide/formoterol is a cost-effective option for the treatment of mild asthma versus regular ICS.

Risk of active tuberculosis among COPD patients treated with fixed combinations of long-acting beta2 agonists and inhaled corticosteroids.

OBJECTIVES: To investigate the incidence of active tuberculosis (TB) among COPD patients using fluticasone/salmeterol or budesonide/formoterol, and to identify any differences between these two groups of patients. METHODS: The study enrolled COPD patients from Taiwan NHIRD who received treatment with fluticasone/salmeterol or budesonide/formoterol for > 90 days between 2004 and 2011. The incidence of active TB was the primary outcome. RESULTS: Among the intention-to-treat population prior to matching, the incidence rates of active TB were 0.94 and 0.61% in the fluticasone/salmeterol and budesonide/formoterol groups, respectively. After matching, the fluticasone/salmeterol group had significantly higher rates of active TB (adjusted HR, 1.41, 95% CI, 1.17-1.70) compared with the budesonide/formoterol group. The significant difference between these two groups remained after a competing risk analysis (HR, 1.45, 95% CI, 1.21-1.74). Following propensity score matching, the fluticasone/salmeterol group had significantly higher rates of active TB compared with the budesonide/formoterol group (adjusted HR, 1.45, 95% CI, 1.14-1.85). A similar trend was observed after a competing risk analysis (HR, 1.44, 95% CI, 1.19-1.75). A higher risk of active TB was observed in the fluticasone/salmeterol group compared with the budesonide/formoterol group across all subgroups, but some differences did not reach statistical significance. CONCLUSION: Fluticasone/salmeterol carried a higher risk of active TB compared with budesonide/formoterol among COPD patients.

Comparing the efficacy and safety of formoterol/budesonide pMDI versus its mono-components and other LABA/ICS in patients with asthma.

INTRODUCTION: Pressurised metered dose inhalers (pMDIs) are effective drug delivery devices prescribed in obstructive airway diseases due to their convenience, portability, ease of enabling multiple doses in a single formulation, and storage in any orientation. For the management of asthma, the fixed-dose combination of a long-acting ß2-agonist (LABA) and an inhaled corticosteroid (ICS) has been recommended by Global Initiative for Asthma guideline as a preferred treatment option for patients who are uncontrolled with only ICS doses. One of the available LABA/ICS combinations is the formoterol/budesonide (FB). AREAS COVERED: This article systematically reviews the efficacy and safety of the FB pMDI compared with the FB dry powder inhaler (DPI), individual mono-components (formoterol and budesonide) or salmeterol/fluticasone (SF) combination in the treatment of asthma among paediatric and adult patients. PubMed was searched with the string: ''((Budesonide) AND Formoterol) AND ((((pMDI) OR MDI) OR Pressurised Metered-dose inhaler) OR Metered-dose inhaler)'', in ALL fields. Screening of all the articles was done till February 2020. We have included 24 articles from the total of 142 hits received. CONCLUSIONS: The FB pMDI is efficacious for the long-term management of asthma in patients 6 years of age and above. It has been shown to improve lung function and asthma control, and to reduce daytime and night-time symptoms, the number of rescue medication doses and asthma exacerbations. It also showed rapid onset of bronchodilatory effect with a dose-response relationship that allows patients to utilise it as a Single Maintenance And Reliever Therapy (SMART) regimen.

Impact of a change of bronchodilator medications in a hospital drug formulary on intra- and out-of-hospital drug prescriptions: interrupted time series design with comparison group.

BACKGROUND: Hospital drug formularies are reduced lists of drugs designed to optimise inpatient care. Adherence to the drugs included in such formularies is not always 100% but is generally very high. Little research has targeted the impact of a change in these formularies on outpatient drug prescriptions. This study therefore sought to evaluate the impact of a change affecting bronchodilator medications in a hospital drug formulary on intra- and out-of-hospital drug prescriptions in a region in north-western Spain. Two new drugs belonging to this same class were brought onto the out-of-hospital market, overlapping with the intervention. METHODS: We used a natural before-after quasi-experimental design with control group based on monthly data. The intervention evaluated was the modification of a hospital drug formulary, which involved withdrawing salmeterol/fluticasone in order to retain formoterol/budesonide as the sole inhaled corticosteroid and long-acting beta-agonist (ICS/LABA). Using official data sources, we extracted the following dependent variables: defined daily doses (DDD) per 1000 inhabitants per day, DDD per 100 bed-days, and cost per DDD. RESULTS: Intra-hospital use showed a 173.2% rise (95% CI 47.3-299.0%) in the medication retained in the formulary, formoterol/budesonide, and a 94.9% drop (95% CI 77.9-111.9%) in the medication withdrawn from the formulary, salmeterol/fluticasone. This intervention led to an immediate reduction of 75.9% (95% CI 82.8-68.9%) in the intra-hospital cost per DDD of ICS/LABA. No significant changes were observed in out-of-hospital use. CONCLUSIONS: Although this intervention was cost-effective in the intra-hospital setting, the out-of-hospital impact of a change in the drug formulary cannot be generalised to all types of medications and situations.

Once-daily single-inhaler versus twice-daily multiple-inhaler triple therapy in patients with COPD: lung function and health status results from two replicate randomized controlled trials.

BACKGROUND: The comparative efficacy of inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist (ICS/LAMA/LABA) triple therapy administered via single or multiple inhalers in patients with chronic obstructive pulmonary disease (COPD) has not been evaluated comprehensively. We conducted two replicate trials comparing single- with multiple-inhaler ICS/LAMA/LABA combination in COPD. METHODS: 207608 and 207609 were Phase IV, 12-week, randomized, double-blind, triple-dummy non-inferiority trials comparing once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg via Ellipta inhaler, with twice-daily budesonide/formoterol (BUD/FOR) 400/12 µg via metered-dose inhaler plus once-daily tiotropium (TIO) 18 µg via HandiHaler. Patients had symptomatic COPD and forced expiratory volume in 1 s (FEV1) < 50% predicted, or FEV1 < 80% predicted and ≥ 2 moderate or 1 severe exacerbations in the prior year. The primary endpoint in both trials was weighted mean change from baseline (wmCFB) in 0-24-h FEV1 at Week 12. Secondary endpoints included CFB in trough FEV1 at Day 84 and 85. Other endpoints included serial FEV1 and health status outcomes at Week 12. Safety was evaluated descriptively. RESULTS: The modified per-protocol population included 720 and 711 patients in studies 207608 and 207609 (intent-to-treat population: 728 and 732). FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 (Study 207608 treatment difference [95% confidence interval]: 15 mL [- 13, 43]; Study 207609: 11 mL [- 20, 41]). FF/UMEC/VI improved trough FEV1 CFB versus BUD/FOR+TIO at Day 84 and 85 (Day 85 treatment difference: Study 207608: 38 mL [10, 66]; Study 207609: 51 mL [21, 82]) and FEV1 at 12 and 24 h post-morning dose at Week 12 in both studies. No treatment differences were seen in health status outcomes. Safety profiles were similar between treatments; pneumonia occurred in 7 (< 1%) patients with FF/UMEC/VI and 9 (1%) patients with BUD/FOR+TIO, across both studies. CONCLUSIONS: FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 in patients with COPD. Greater improvements in trough and serial FEV1 measurements at Week 12 with FF/UMEC/VI versus BUD/FOR+TIO, together with similar health status improvements and safety outcomes including the incidence of pneumonia, suggest that once-daily single-inhaler FF/UMEC/VI triple therapy is a viable option for patients looking to simplify their treatment regimen. TRIAL REGISTRATION: GSK (207608/207609; NCT03478683/NCT03478696).

Triple Therapy with Budesonide/Glycopyrrolate/Formoterol Fumarate Improves Inspiratory Capacity in Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap.

Purpose: Asthma-chronic obstructive pulmonary disease overlap (ACO), characterized by airway limitation, is an important condition with high incidence and mortality. Although some guidelines recommend triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting ß2 agonists, this treatment approach is based on the extrapolation of data from studies of asthma or chronic obstructive pulmonary disease (COPD) alone. Methods: A 12-week, randomized, open-label cross-over pilot study was conducted in 19 patients with ACO to investigate the effect of triple therapy with glycopyrrolate (GLY) 50 µg/day on budesonide/formoterol fumarate (BUD/FORM) 640/18 µg/day. The study period included a 4-week wash-out, 4-week run-in, and 4-week treatment period. Respiratory function tests, fractional exhaled nitric oxide (FeNO), a COPD assessment test (CAT) and an asthma control questionnaire (ACQ) were carried out 0, 4, and 8 weeks after randomization. Results: A total of 19 patients with stable ACO (19 males and no females) with a mean age of 70.7 ± 7.6 years (± standard deviation, SD; range 55-83 years) participated in this study. All patients were ex-smokers with a smoking history of 63.1 ± 41.1 pack-years (± SD). Mean values for inspiratory capacity (IC), an index of hyperinflation of the lung that causes exertional dyspnea and reduced exercise, were 1.93 L (± 0.47 L) after the run-in, 1.85 L (± 0.51 L) after the BUD/FORM dual therapy period and 2.11 L (± 0.58 L) after the BUD/GLY/FORM triple therapy period. IC values after the BUD/GLY/FORM triple therapy were significantly higher than those after the run-in (p < 0.02). FeNO values, ACQ, and CAT scores were not significantly different among the run-in, wash-out, and triple-therapy periods. Conclusion: The present pilot study showed that triple therapy with BUD/GLY/FORM results in an improvement in lung function parameters including IC, indicating the potential value of triple therapy as standard treatment for ACO.

The dry powder inhaler features of the Easyhaler that benefit the management of patients.

Introduction: Inhaled therapies are likely to continue to dominate asthma and chronic obstructive pulmonary disease treatment. Dry powder inhalers (DPIs) have several advantages over pressurized metered-dose inhaler (pMDIs), that are most frequently marketed world-wide, but often difficult to use. This literature search focus on DPI features, with respect to Easyhaler, that may affect their use and patients' clinical benefit.Areas covered: DPIs are breath-actuated, easy to use, convenient to use, and more environmentally friendly. During inhalation, the formulation in a DPI is disaggregated by a turbulent airflow energy to generate particles with the greatest likelihood of deposition into the airways. The resistance among DPIs varies from low to high and those with high resistance are wrongly considered as difficult to use. Multidose reservoir-type DPIs have been developed to efficiently deliver a wide range of medications, including the fixed-dose combination of budesonide and formoterol. Easyhaler® shares a similar shape with pMDIs and, as other DPIs, its performance is unaffected by environmental and storage conditions. Due to Easyhaler internal design, dose emission is consistent irrespective of the inhalation flow used by each patient.Expert opinion: Easyhaler® may be considered one of the most convenient inhalers, for daily use, in patients with asthma or COPD.

Reduced risk of clinically important deteriorations by ICS in COPD is eosinophil dependent: a pooled post-hoc analysis.

BACKGROUND: Clinically Important Deterioration (CID) is a novel composite measure to assess treatment effect in chronic obstructive pulmonary disease (COPD). We examined the performance and utility of CID in assessing the effect of inhaled corticosteroids (ICS) in COPD. METHODS: This post-hoc analysis of four budesonide/formoterol (BUD/FORM) studies comprised 3576 symptomatic moderate-to-very-severe COPD patients with a history of exacerbation. Analysis of time to first CID event (exacerbation, deterioration in forced expiratory volume in 1 second [FEV1] or worsening St George's Respiratory Questionnaire [SGRQ] score) was completed using Cox proportional hazards models. RESULTS: The proportion of patients with ≥1 CID in the four studies ranged between 63 and 77% and 69-84% with BUD/FORM and FORM, respectively, with an average 25% reduced risk of CID with BUD/FORM. All components contributed to the CID event rate. Experiencing a CID during the first 3 months was associated with poorer outcomes (lung function, quality of life, symptoms and reliever use) and increased risk of later CID events. The effect of BUD/FORM versus FORM in reducing CID risk was positively associated with the blood eosinophil count. CONCLUSIONS: Our findings suggest that BUD/FORM offers protective effects for CID events compared with FORM alone, with the magnitude of the effect dependent on patients' eosinophil levels. CID may be an important tool for evaluation of treatment effect in a complex, multifaceted, and progressive disease like COPD, and a valuable tool to allow for shorter and smaller future outcome predictive trials in early drug development.

Metabolic and cardiorespiratory effects of decreasing lung hyperinflation with budesonide/formoterol in COPD: a randomized, double-crossover, placebo-controlled, multicenter trial.

BACKGROUND: Studies suggest that acute decreases in lung hyperinflation at rest improves cardiac function and increases lung vascular perfusion from decompression of a compromised heart. In those studies, changes in resting oxygen uptake induced by medications, an alternative explanation for compensatory increased cardiac function, were not explored. METHODS: This double-blind, multicenter, double-crossover study enrolled adults with chronic obstructive pulmonary disease, resting hyperinflation, and > 10% improvement in inspiratory capacity after 2 inhalations of budesonide/formoterol 160/4.5 µg. Metabolic, cardiac, and ventilatory function were measured 60 min pre-/post-dose at each visit. Primary endpoint was change in resting oxygen uptake for budesonide/formoterol versus placebo. RESULTS: Fifty-one patients (median age: 63 years) received treatment. Compared with placebo, budesonide/formoterol significantly increased resting oxygen uptake (mean change from baseline: 1.25 vs 11.37 mL/min; P = 0.007) as well as tidal volume and minute ventilation. This occurred despite improvements in the inspiratory capacity, forced vital capacity, and expiratory volume in 1 s. No significant treatment differences were seen for oxygen saturation, respiratory rate, and resting dyspnea. There was a numerical increase in oxygen pulse (oxygen uptake/heart rate). Correlations between inspiratory capacity and oxygen pulse were weak. CONCLUSIONS: Budesonide/formoterol treatment in resting hyperinflated patients with COPD results in significant deflation. The increase in oxygen uptake and minute ventilation at lower lung volumes, without changes in heart rate and with minimal improvement in oxygen pulse, suggests increased oxygen demand as a contributor to increased cardiac function. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02533505.

DuoResp® Spiromax® adherence, satisfaction and ease of use: findings from a multi-country observational study in patients with asthma and COPD in Europe (SPRINT).

Objective: Adherence and inhaler technique are often suboptimal in asthma and chronic obstructive pulmonary disease (COPD). New inhalers have been developed to improve these determinants of treatment effectiveness. We assessed treatment adherence, satisfaction, and ease of use of DuoResp® Spiromax® among SPRINT study participants.Methods: The Phase IV SPRINT study was conducted in 10 European countries. Asthma and COPD patients were receiving a fixed-dose combination of inhaled corticosteroid (ICS) and long-acting ß2-agonist (LABA), delivered via various inhalers including DuoResp Spiromax. DuoResp Spiromax users self-assessed adherence using the 8-item Morisky Medication Adherence Scale (MMAS-8®), and ease of use and satisfaction using 10-point scales, during a single physician's office visit.Results: Of 1661 (asthma: n = 1101; COPD: n = 560) SPRINT study participants, 342 (asthma: n = 235; COPD: n = 107) received DuoResp Spiromax prior to inclusion. Overall, 72.5% of DuoResp Spiromax users reported medium or high adherence (MMAS-8 score ≥6). Mean (standard deviation [SD]) satisfaction score for DuoResp Spiromax was 8.9 (1.6). Almost all (98.8%) DuoResp Spiromax users were at least satisfied with their inhaler; 85.4% were very satisfied. Mean (SD) ease of use score for DuoResp Spiromax was 9.1 (1.3).Conclusions: Asthma and COPD patients using DuoResp Spiromax reported moderate-to-high medication adherence, were very satisfied with their inhaler and found it easy to use.

Comparative Safety Profile of the Fixed-Dose Combination Corticosteroid and Long-acting ß2-Agonist Fluticasone Propionate/Formoterol Fumarate: A 36-Month Longitudinal Cohort Study in UK Primary Care.

OBJECTIVE: The inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) fluticasone propionate/formoterol fumarate (FP/FORM; Flutiform®) has been available as fixed-dose combination (FDC) therapy for asthma patients aged ≥ 12 years in the UK since 2012. This post-authorisation safety study examined adverse outcomes and prescribing practices for FP/FORM and other FDC ICS/LABA therapies in a real-life clinical setting over 36 months. METHODS: Historical, longitudinal cohort database study using UK primary care data from the Clinical Practice Research Datalink (CPRD) database, for patients initiated on or switched to an FDC ICS/LABA (ENCePP study number: EUPAS12330). The main cohort was adults aged ≥ 18 years with asthma. The primary outcome was incidence of new adverse outcomes after initiation of ICS/LABA; hazard ratios (HRs) and 95% confidence intervals were estimated for FP/FORM versus other FDC ICS/LABAs using Cox regression models. RESULTS: A total of 241,007 patients with an FDC ICS/LABA prescription were identified. In the adult asthma cohort (N = 41,609), the incidence rate of new adverse outcomes [in 100 patient-years (py)] was significantly lower for FP/FORM (24.75) versus fluticasone/salmeterol metered-dose inhaler [8.86; HR 1.14 (1.04, 1.25)], fluticasone/salmeterol dry powder inhaler [31.19; HR 1.18 (1.08, 1.29)], budesonide/formoterol [25.16; HR: 1.13 (1.03, 1.25)] and beclometasone/formoterol [25.47; HR 1.14 (1.04, 1.25)]. The overall prescribing rate was lower for FP/FORM (13.85 per 1000/py) than licensed FDC ICS/LABA comparators (20.30-28.13 per 1000/py). Of those prescribed FP/FORM, 80.8% were adults with asthma and < 7% were prescribed FP/FORM "off-label". CONCLUSIONS: The results suggest that FP/FORM was associated with an overall lower adverse outcome rate than the licensed comparators.