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Withdrawal of inhaled corticosteroids versus continuation of triple therapy in patients with COPD in real life: observational comparative effectiveness study.
Magnussen, H, Lucas, S, Lapperre, T, Quint, JK, Dandurand, RJ, Roche, N, Papi, A, Price, D, Miravitlles, M, ,
Respiratory research. 2021;(1):25
Abstract
BACKGROUND Inhaled corticosteroids (ICS) are indicated for prevention of exacerbations in patients with COPD, but they are frequently overprescribed. ICS withdrawal has been recommended by international guidelines in order to prevent side effects in patients in whom ICS are not indicated. METHOD Observational comparative effectiveness study aimed to evaluate the effect of ICS withdrawal versus continuation of triple therapy (TT) in COPD patients in primary care. Data were obtained from the Optimum Patient Care Research Database (OPCRD) in the UK. RESULTS A total of 1046 patients who withdrew ICS were matched 1:4 by time on TT to 4184 patients who continued with TT. Up to 76.1% of the total population had 0 or 1 exacerbation the previous year. After controlling for confounders, patients who discontinued ICS did not have an increased risk of moderate or severe exacerbations (adjusted HR: 1.04, 95% confidence interval (CI) 0.94-1.15; p = 0.441). However, rates of exacerbations managed in primary care (incidence rate ratio (IRR) 1.33, 95% CI 1.10-1.60; p = 0.003) or in hospital (IRR 1.72, 95% CI 1.03-2.86; p = 0.036) were higher in the cessation group. Unsuccessful ICS withdrawal was significantly and independently associated with more frequent courses of oral corticosteroids the previous year and with a blood eosinophil count ≥ 300 cells/μL. CONCLUSIONS In this primary care population of patients with COPD, composed mostly of infrequent exacerbators, discontinuation of ICS from TT was not associated with an increased risk of exacerbation; however, the subgroup of patients with more frequent courses of oral corticosteroids and high blood eosinophil counts should not be withdrawn from ICS. Trial registration European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS30851).
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Effect of Nebulized Magnesium vs Placebo Added to Albuterol on Hospitalization Among Children With Refractory Acute Asthma Treated in the Emergency Department: A Randomized Clinical Trial.
Schuh, S, Sweeney, J, Rumantir, M, Coates, AL, Willan, AR, Stephens, D, Atenafu, EG, Finkelstein, Y, Thompson, G, Zemek, R, et al
JAMA. 2020;(20):2038-2047
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IMPORTANCE While intravenous magnesium decreases hospitalizations in refractory pediatric acute asthma, it is variably used because of invasiveness and safety concerns. The benefit of nebulized magnesium to prevent hospitalization is unknown. OBJECTIVE To evaluate the effectiveness of nebulized magnesium in children with acute asthma remaining in moderate or severe respiratory distress after initial therapy. DESIGN, SETTING, AND PARTICIPANTS A randomized double-blind parallel-group clinical trial from September 26, 2011, to November 19, 2019, in 7 tertiary-care pediatric emergency departments in Canada. The participants were otherwise healthy children aged 2 to 17 years with moderate to severe asthma defined by a Pediatric Respiratory Assessment Measure (PRAM) score of 5 or greater (on a 12-point scale) after a 1-hour treatment with an oral corticosteroid and 3 inhaled albuterol and ipratropium treatments. Of 5846 screened patients, 4332 were excluded for criteria, 273 declined participation, 423 otherwise excluded, 818 randomized, and 816 analyzed. INTERVENTIONS Participants were randomized to 3 nebulized albuterol treatments with either magnesium sulfate (n = 410) or 5.5% saline placebo (n = 408). MAIN OUTCOMES AND MEASURES The primary outcome was hospitalization for asthma within 24 hours. Secondary outcomes included PRAM score; respiratory rate; oxygen saturation at 60, 120, 180, and 240 minutes; blood pressure at 20, 40, 60, 120, 180, and 240 minutes; and albuterol treatments within 240 minutes. RESULTS Among 818 randomized patients (median age, 5 years; 63% males), 816 completed the trial (409 received magnesium; 407, placebo). A total of 178 of the 409 children who received magnesium (43.5%) were hospitalized vs 194 of the 407 who received placebo (47.7%) (difference, -4.2%; absolute risk difference 95% [exact] CI, -11% to 2.8%]; P = .26). There were no significant between-group differences in changes from baseline to 240 minutes in PRAM score (difference of changes, 0.14 points [95% CI, -0.23 to 0.50]; P = .46); respiratory rate (0.17 breaths/min [95% CI, -1.32 to 1.67]; P = .82); oxygen saturation (-0.04% [95% CI, -0.53% to 0.46%]; P = .88); systolic blood pressure (0.78 mm Hg [95% CI, -1.48 to 3.03]; P = .50); or mean number of additional albuterol treatments (magnesium: 1.49, placebo: 1.59; risk ratio, 0.94 [95% CI, 0.79 to 1.11]; P = .47). Nausea/vomiting or sore throat/nose occurred in 17 of the 409 children who received magnesium (4%) and 5 of the 407 who received placebo (1%). CONCLUSIONS AND RELEVANCE Among children with refractory acute asthma in the emergency department, nebulized magnesium with albuterol, compared with placebo with albuterol, did not significantly decrease the hospitalization rate for asthma within 24 hours. The findings do not support use of nebulized magnesium with albuterol among children with refractory acute asthma. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01429415.
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24-Hour Serial Spirometric Assessment of Once-Daily Fluticasone Furoate/Umeclidinium/Vilanterol Versus Twice-Daily Budesonide/Formoterol in Patients with COPD: Analysis of the FULFIL Study.
Lipson, DA, Birk, R, Brealey, N, Zhu, CQ
Advances in therapy. 2020;(12):4894-4909
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INTRODUCTION Few studies have utilized 24-h serial spirometry to compare the effects of inhaled chronic obstructive pulmonary disease (COPD) therapies on lung function. The FULFIL study previously reported significant lung function improvements with once-daily single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus twice-daily single-inhaler budesonide/formoterol (BUD/FOR) in patients with symptomatic COPD at risk of exacerbations. METHODS This prespecified analysis evaluated 24-h serial spirometry data from a subgroup of 406 patients in FULFIL. BUD/FOR twice-daily dosing was maintained during 24-h spirometry. A post hoc analysis evaluated serial forced expiratory volume in 1 s (FEV1) at day 1 and week 24 by disease severity at screening (FEV1 < 50% predicted and no moderate or severe exacerbation in prior year, FEV1 < 50% predicted and ≥ 1 moderate or severe exacerbation in prior year, and FEV1 ≥ 50% and < 80% predicted and ≥ 2 moderate or ≥ 1 severe exacerbations in prior year). RESULTS Odds of achieving a ≥ 100-mL increase from baseline in FEV1 within the first 6 h post dose on day 1 were significantly greater with FF/UMEC/VI than BUD/FOR [odds ratio 2.79 (95% confidence interval 1.56-4.98); p < 0.001]. FF/UMEC/VI led to greater improvements in weighted mean FEV1 over 0-6, 0-12, 0-24, and 12-24 h on day 1 and at week 24, with the greatest between-group differences at week 24 (range 196-210 mL; all p < 0.001). Significant between-treatment differences in FEV1 and forced vital capacity (FVC) in favor of FF/UMEC/VI versus BUD/FOR were seen at all time points at week 24 (FEV1 range 156-231 mL, all p < 0.001; FVC range 139-309 mL, all p ≤ 0.002). Serial FEV1 results were consistent irrespective of disease severity at screening. CONCLUSION These findings further demonstrate sustained lung function benefits with once-daily FF/UMEC/VI single-inhaler triple therapy in patients with symptomatic COPD at risk of exacerbations across a range of disease severities.
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Intracellular interactions of umeclidinium and vilanterol in human airway smooth muscle.
Shaikh, N, Johnson, M, Hall, DA, Chung, KF, Riley, JH, Worsley, S, Bhavsar, PK
International journal of chronic obstructive pulmonary disease. 2017;:1903-1913
Abstract
BACKGROUND Intracellular mechanisms of action of umeclidinium (UMEC), a long-acting muscarinic receptor antagonist, and vilanterol (VI), a long-acting β2-adrenoceptor (β2R) agonist, were investigated in target cells: human airway smooth-muscle cells (ASMCs). MATERIALS AND METHODS ASMCs from tracheas of healthy lung-transplant donors were treated with VI, UMEC, UMEC and VI combined, or control compounds (salmeterol, propranolol, ICI 118.551, or methacholine [MCh]). Cyclic adenosine monophosphate (cAMP) was measured using an enzyme-linked immunosorbent assay, intracellular free calcium ([Ca2+]i) using a fluorescence assay, and regulator of G-protein signaling 2 (RGS2) messenger RNA using real-time quantitative polymerase chain reaction. RESULTS VI and salmeterol (10-12-10-6 M) induced cAMP production from ASMCs in a concentration-dependent manner, which was greater for VI at all concentrations. β2R antagonism by propranolol or ICI 118.551 (10-12-10-4 M) resulted in concentration-dependent inhibition of VI-induced cAMP production, and ICI 118.551 was more potent. MCh (5×10-6 M, 30 minutes) attenuated VI-induced cAMP production (P<0.05), whereas pretreatment with UMEC (10-8 M, 1 hour) restored the magnitude of VI-induced cAMP production. ASMC stimulation with MCh (10-11-5×10-6 M) resulted in a concentration-dependent increase in [Ca2+]i, which was attenuated with UMEC pretreatment. Reduction of MCh-induced [Ca2+]i release was greater with UMEC + VI versus UMEC. UMEC enhanced VI-induced RGS2 messenger RNA expression. CONCLUSION These data indicate that UMEC reverses cholinergic inhibition of VI-induced cAMP production, and is a more potent muscarinic receptor antagonist when in combination with VI versus either alone.
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Comparative Meta-Analysis of the Efficacy of Once-Daily Fluticasone Furoate 100 µG Versus Twice-Daily Fluticasone Propionate 250 µG in Adolescents and Adults with Persistent Asthma.
Tomlinson, R, Parks, D, Martin, A
Lung. 2017;(5):571-574
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Fluticasone furoate and fluticasone propionate are recommended options for prophylactic maintenance treatment of persistent asthma. Using data from two previous clinical studies (GSK studies: FFA109685/NCT00603278, FFA112059/NCT01159912), this meta-analysis compared change from baseline in clinic visit mean trough forced expiratory volume in 1 s (FEV1) with fluticasone furoate 100 µg once-daily (FF100) versus fluticasone propionate 250 µg twice-daily (FP250) in adolescents and adults with persistent asthma. Using a DerSimonian-Laird random-effects model (primary meta-analysis), there was no statistically significant difference between FF100 and FP250 in change from baseline in trough FEV1 (-1.7 mL [95% CI -80.4, +77.0], p = 0.9664) and FF100 was non-inferior to FP250. Supporting analyses using least squares mean and fixed-effects model approaches produced similar findings. In this analysis, FF100 and FP250 demonstrated a comparable treatment effect on trough FEV1 in patients aged ≥12 years with persistent asthma; however, results interpretation should consider study design and methodological limitations.
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The use of multiple respiratory inhalers requiring different inhalation techniques has an adverse effect on COPD outcomes.
Bosnic-Anticevich, S, Chrystyn, H, Costello, RW, Dolovich, MB, Fletcher, MJ, Lavorini, F, Rodríguez-Roisin, R, Ryan, D, Wan Yau Ming, S, Price, DB
International journal of chronic obstructive pulmonary disease. 2017;:59-71
Abstract
BACKGROUND Patients with COPD may be prescribed multiple inhalers as part of their treatment regimen, which require different inhalation techniques. Previous literature has shown that the effectiveness of inhaled treatment can be adversely affected by incorrect inhaler technique. Prescribing a range of device types could worsen this problem, leading to poorer outcomes in COPD patients, but the impact is not yet known. AIMS To compare clinical outcomes of COPD patients who use devices requiring similar inhalation technique with those who use devices with mixed techniques. METHODS A matched cohort design was used, with 2 years of data from the Optimum Patient Care Research Database. Matching variables were established from a baseline year of follow-up data, and two cohorts were formed: a "similar-devices cohort" and a "mixed-devices cohort". COPD-related events were recorded during an outcome year of follow-up. The primary outcome measure was an incidence rate ratio (IRR) comparing the rate of exacerbations between study cohorts. A secondary outcome compared average daily use of short-acting beta agonist (SABA). RESULTS The final study sample contained 8,225 patients in each cohort (mean age 67 [SD, 10], 57% males, 37% current smokers). Patients in the similar-devices cohort had a lower rate of exacerbations compared with those in the mixed-devices cohort (adjusted IRR 0.82, 95% confidence interval [CI] 0.80-0.84) and were less likely to be in a higher-dose SABA group (adjusted proportional odds ratio 0.54, 95% CI 0.51-0.57). CONCLUSION COPD patients who were prescribed one or more additional inhaler devices requiring similar inhalation techniques to their previous device(s) showed better outcomes than those who were prescribed devices requiring different techniques.
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Zinc sulphate for acute bronchiolitis: A double-blind placebo-controlled trial.
Mahyar, A, Ayazi, P, Ahmadi, NK, Pour Nikoo, ST, Hamzehloo, S, Taremiha, A, Yazdi, Z, Esmaeily, S
Le infezioni in medicina. 2016;(4):331-336
Abstract
The use of adjunctive therapies to achieve rapid recovery from clinical symptoms of acute bronchiolitis would appear necessary. This study was performed to determine the effect of zinc sulphate on treating acute bronchiolitis. In this study, 100 children affected with acute bronchiolitis were investigated. Fifty patients received oral zinc sulphate and 50 patients placebo. Signs and symptoms of the disease were compared between two groups at the time of admission and then 24, 48, 72, 96 and 120 hours after the beginning of treatment. The trend of recovery of clinical signs and symptoms was more favourable in the case group than in the control group in 24, 48, 72, 96 and 120 hours after beginning of the treatment. The significant differences were observed between the two groups in terms of improvements in coughing and wheezing 48 and 72 hours after the beginning of the treatment (P<0.05). Full recovery was observed in 49 (98%) patients receiving zinc sulphate within 72 hours of the beginning of treatment (P=0.0001). The present study showed that administration of zinc sulphate accelerates improvement from clinical signs and symptoms of acute bronchiolitis. Thus we recommend the use of zinc sulphate for the treatment of acute bronchiolitis.
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Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of Albuterol (Salbuterol) Multi-dose Dry-Powder Inhaler and ProAir(®) Hydrofluoroalkane for the Treatment of Persistent Asthma: Results of Two Randomized Double-Blind Studies.
Kerwin, EM, Taveras, H, Iverson, H, Wayne, D, Shah, T, Lepore, MS, Miller, DS
Clinical drug investigation. 2016;(1):55-65
Abstract
BACKGROUND AND OBJECTIVE Metered-dose inhalers require patients to coordinate inhalation with actuation. The present albuterol multi-dose dry-powder inhaler (mDPI) does not require patients to coordinate inspiration with actuation, thereby simplifying delivery of albuterol to the lungs. The aim of the present study was to compare the efficacy, pharmacokinetics, pharmacodynamics, extrapulmonary pharmacodynamics, and safety of albuterol (salbuterol) delivered via a ProAir® hydrofluoroalkane (HFA) metered-dose inhaler and an mDPI. METHODS Two double-blind, randomized, double-dummy, crossover, multicenter, placebo-controlled studies in persistent asthma patients were conducted. Study 1: 47 adult patients were treated with cumulative doses of albuterol mDPI or ProAir HFA (90 µg/inhalation; 1 + 1 + 2 + 4 + 8 inhalations) or placebo. Study 2: 71 patients aged ≥12 years were randomly assigned to receive 90 or 180 μg of albuterol mDPI or ProAir HFA, or placebo. Primary efficacy endpoints were baseline-adjusted forced expiratory volume in 1 s (FEV1) at 30 min (30-min FEV1) after each cumulative dose (Study 1) and FEV1 area under the effect curve over 6 h (FEV1 AUEC0-6) after dosing (Study 2). RESULTS Study 1: differences, with corresponding 90% confidence intervals, between albuterol mDPI and ProAir HFA in FEV1 after each cumulative dose and in FEV1 AUEC0-6 after the final dose were within pre-established equivalence limits. The difference in FEV1 at high vs. low doses was significant for both active treatments (p < 0.0001). Active treatments were similar in systemic exposure, extrapulmonary pharmacodynamics, and safety. Study 2: mean FEV1 AUEC0-6 was significantly greater than for placebo for both doses of albuterol mDPI and ProAir HFA (p < 0.0001). Albuterol mDPI was comparable to ProAir HFA at 90 and 180 µg. Both study treatments were generally well tolerated. CONCLUSION The bronchodilatory efficacy and pharmacokinetic/pharmacodynamic profiles of albuterol mDPI and ProAir HFA are comparable, with a safety profile consistent with that of inhaled albuterol.
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The efficacy of nebulized salbutamol, magnesium sulfate, and salbutamol/magnesium sulfate combination in moderate bronchiolitis.
Kose, M, Ozturk, MA, Poyrazoğlu, H, Elmas, T, Ekinci, D, Tubas, F, Kurt, T, Goktas, MA
European journal of pediatrics. 2014;(9):1157-60
Abstract
UNLABELLED The aim of this paper is to compare the effect of nebulized magnesium sulfate to nebulized salbutamol and salbutamol/magnesium sulfate on successful discharge from the emergency department. A total of 56 infants were included in this double-blinded, prospective study. Infants were grouped according to the nebulized treatment they received: group 1-salbutamol/normal saline, group 2-magnesium sulfate and normal saline, and group 3-salbutamol plus magnesium sulfate. Heart beat, bronchiolitis, clinical severity scores (CSS), and oxygen saturation of the patients were determined before and after nebulization (0, 1, 4 h). The patients were monitored for adverse reactions. Post-treatment mean CSS results were significantly lower than pre-treatment scores in all groups at 4 h with no significant difference within groups. CSS scores were lower in the salbutamol/magnesium sulfate group when compared with the magnesium sulfate and salbutamol groups (3.4 (2.4-4.3), 4.7 (3.8-5.7), 4.0 (3.2-4.3)). CSS were significantly lower than those from the magnesium sulfate group. CONCLUSION Nebulized magnesium sulfate plus salbutamol may have additive effects for improving the short-term CSS.
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Montelukast versus budesonide as a first line preventive therapy in mild persistent asthma in 2 to 18 y.
Shah, MB, Gohil, J, Khapekar, S, Dave, J
Indian journal of pediatrics. 2014;(7):655-9
Abstract
OBJECTIVES To compare the efficacy of oral Montelukast and inhaled Budesonide as a first line preventive therapy in mild persistent asthma in age group 2-18 y. METHODS This prospective randomized controlled clinical study was conducted for 12 wk. Sixty patients of mild persistent asthma aged 2 to 18 y were randomly allocated to either oral Montelukast (n = 60) or inhaled Budesonide (n = 60) group. Outcomes measured were improvement in peak expiratory flow rate (PEFR), forced expiratory volume 1 s/forced vital capacity (FEV1/FVC), day time and night time symptoms and frequency of exacerbations and need to change medications. RESULTS There was significant improvement in PEFR, FEV1/FVC, day time and night time symptoms and frequency of exacerbations in both groups. However, more significant improvement in FEV1/FVC (CI 95 %, p = 0.029) and day time symptoms (CI 95 %, p = 0.002) was seen in Budesonide group compared to Montelukast group. CONCLUSIONS The present study suggests that oral Montelukast is not inferior to Budesonide in treatment of mild persistent asthma in 2 to 18 y children in terms of control of symptoms and improvement in pulmonary function tests over a 12 wk period. However, there was more significant improvement in day time symptoms, more significant increase in FEV1/FVC ratio and less exacerbation in patients receiving Budesonide compared to those receiving Montelukast. However, side effects due to long term use of steroids such as growth stunting and bone osteopenia should also be considered before recommending. Trial registered at CTRI no. REF/2012/09/004035.