Long-acting Beta2-agonist Combination Research Articles

Impact of pharmacotherapy with tiotropium/olodaterol on the pulmonary function in COPD patients depending on the Arg16Gly polymorphism of ADRB2 gene

Annotation. Chronic obstructive pulmonary disease (COPD) is a prevalent chronic disease. Endogenic or genetic factors play a significant role in the COPD development. The aim of our study was to investigate a response to the tiotropium/olodaterol treatment in patients with different ADRB2 gene polymorphism. 100 patients with the diagnosis of COPD were included into the study. Pulmonary function testing was performed during all study visits. All patients received treatment according to GOLD 2019, which included a combination of long-acting beta-2 agonists (LABA) and long-acting muscarinic antagonists (LAMA). According to the results of genetic testing all patients were divided into 3 groups: Arg16Arg – 23 patients (23%), Arg16Gly – 39 patients (39%), Gly16Gly – 38 patients (38%). Statistical processing of research materials was carried out using the SPSS statistical program package for Windows version 26.0. Descriptive statistics were determined for each interval variable and presented as mean ± standard deviation (SD). Kolmogorov-Smirnov test, Mann-Whitney test and T-test, Wilkson test, t-test, Kruskal-Wallis test were used as part of the one-way ANOVA analysis, as well as with the analysis of covariance (ANCOVA) followed by pairwise comparison of groups using Bonferroni corrections. Groups did not differ by sex, age, part of smokers, COPD duration. There was significant difference in RLM at the time of inclusion (p=0.01). There was a significant difference in the Pain value at the time of study completion (р=0.024). When comparing values of SGRQ questionnaire, there was a significant difference in the scales of Impact (р=0.006) and Total score (р=0.021). Thus, group Gly16Gly had better dynamics of SF-36 and SGRQ values during the study. Despite the absence of significant difference we can state, that Gly16Gly genotype has better response to treatment when compared to Arg16Arg, which is probably conditioned by the development of sensitization of ADRB2 receptor in Arg16Arg group.

Вплив поліморфізму C79G (rs1072714) та A46G (rs1042713) гена ADRB2 на клінічний перебіг ХОЗЛ

Аbstract. Chronic obstructive pulmonary disease (COPD) is a prevalent disease, that can be prevented and treated. Genetic factors play an important role in the COPD development. The aim of our study was to found ADRB2 gene polymorphism prevalence among patients with COPD, and assessment of its relation with the COPD development and clinical course. Materials and methods. 100 patients with COPD were included into the study. Source documentation, clinical and historical data were collected during study visits. Blood samples for ADRB2 gene testing were taken in all patients. All patients were treated according to GOLD guidelines, which included a combination of long-acting beta-2 agonists and long-acting anticholinergic drugs. According to the genetic analysis all patients were divided into 3 groups C79C/G46G (Haplotype 1) — 23 patients (23 %), C79G/A46G (Haplotype 2) — 26 patients (26 %), G79G/A46A (Haplotype 3) — 26 patients (26 %). Results. In correlation analysis there was a weak negative correlation between Haplotype 1 and total amount of exacerbations (r = -0.245, p = 0.032) and hospitalizations (r = -0.248, p = 0.032), and haplotype 3 had weak positive correlation with the amount of out-patient exacerbations (r = 0.263, p = 0.023). An average amount of antibiotic courses in group 1 was (1.09 ± 0.2), in group 2 — (1.69 ± 0.18), in group 3 — (2.00 ± 0.22), this difference was statistically significant (р = 0.005). There also was a significant difference in the duration of antibiotic treatment, which was (8.61 ± 1.55) in group 1, (12.88 ± 1.62) days in group 2 and (14.42 ± 1.68) days in group 3 (р = 0.036). Conclusions. ADRB2 gene polymorphism affects clinical course of COPD, which manifest in the different need in the administration of antibiotics in study groups, and also in the tendency towards different amount of exacerbations and rate of glucocorticoid use. Key words: COPD, gene ADRB2, exacerbations, antibiotics.

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

ObjectivesTo 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.MethodsThe 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.ResultsAmong 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.ConclusionFluticasone/salmeterol carried a higher risk of active TB compared with budesonide/formoterol among COPD patients.

New opportunities of dual bronchodilation therapy for patients with chronic obstructive pulmonary disease.

Currently, combinations of long-acting beta2-agonists and long-acting anticholinergics are considered as the basic therapy for majority of patients with chronic obstructive pulmonary disease (COPD). These combinations have different pharmacological characteristics and delivery devices that provides different clinical effects and new opportunities for personalized treatment of COPD. Aclidinium/formoterol fixed combination differs from other dual bronchodilators by twice-daily dosing regimen, good safety profile and a specific delivery system. Recent information on clinical efficacy and safety of aclidinium/formoterol combination in COPD patients is given in this article.

Addition of long-acting beta2-agonists to inhaled corticosteroids for chronic asthma in children.

Addition of long-acting beta2-agonists to inhaled corticosteroids for chronic asthma in children.

Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease.

Long-acting bronchodilators, comprising long-acting beta2-agonists (LABA) and long-acting anti-muscarinic agents (LAMA, principally tiotropium), are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease (COPD). Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and LABAs for the treatment of COPD are unclear. To compare the relative effects on markers of quality of life, exacerbations, symptoms, lung function and serious adverse events in people with COPD randomised to LABA plus tiotropium versus tiotropium alone; or LABA plus tiotropium versus LABA alone. We searched the Cochrane Airways Group Specialised Register of trials and ClinicalTrials.gov up to July 2015. We included parallel-group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to LABA against tiotropium or LABA alone for people with COPD. Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials. This review included 10 trials on 10,894 participants, mostly recruiting participants with moderate or severe COPD. All of the trials compared tiotropium in addition to LABA to tiotropium alone, and four trials additionally compared LAMA plus LABA with LABA alone. Four studies used the LABA olodaterol, three used indacaterol, two used formoterol, and one used salmeterol.Compared to tiotropium alone, treatment with tiotropium plus LABA resulted in a slightly larger improvement in mean health-related quality of life (St George's Respiratory Questionnaire (SGRQ) (mean difference (MD) -1.34, 95% confidence interval (CI) -1.87 to -0.80; 6709 participants; 5 studies). The MD was smaller than the four units that is considered clinically important, but a responder analysis indicated that 7% more participants receiving tiotropium plus LABA had a noticeable benefit (greater than four units) from treatment in comparison to tiotropium alone. In the control arm in one study, which was tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with tiotropium plus LABA the improvement was a fall of a further 1.3 units (on average). Most of the data came from studies using olodaterol. High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality).The secondary outcome of pre-bronchodilator forced expiratory volume in one second (FEV1) showed a small mean increase with the addition of LABA over the control arm (MD 0.06, 95% CI 0.05 to 0.07; 9573 participants; 10 studies), which showed a change from baseline ranging from 0.03 L to 0.13 L with tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There was moderate heterogeneity for both exacerbations and withdrawals.This review included data on four LABAs: two administered twice daily (salmeterol, formoterol) and two once daily (indacaterol, olodaterol). The results were largely from studies of olodaterol and there was insufficient information to assess whether the other LABAs were equivalent to olodaterol or each other.Comparing LABA plus tiotropium treatment with LABA alone, there was a small but significant improvement in SGRQ (MD -1.25, 95% CI -2.14 to -0.37; 3378 participants; 4 studies). The data came mostly from studies using olodaterol and, although the difference was smaller than four units, this still represented an increase of 10 people with a clinically important improvement for 100 treated. There was also an improvement in FEV1 (MD 0.07, 95% CI 0.06 to 0.09; 3513 participants; 4 studies), and in addition an improvement in exacerbation rates (odds ratio (OR) 0.80, 95% CI 0.69 to 0.93; 3514 participants; 3 studies). The results from this review indicated a small mean improvement in health-related quality of life and FEV1 for participants on a combination of tiotropium and LABA compared to either agent alone, and this translated into a small increase in the number of responders on combination treatment. In addition, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not. Hospital admission and mortality were not altered by adding LABA to tiotropium, although there may not be enough data. While it is possible that this is affected by higher attrition in the tiotropium group, one would expect that participants withdrawn from the study would have had less favourable outcomes; this means that the expected direction of attrition bias would be to reduce the estimated benefit of the combination treatment. The results were largely from studies of olodaterol and there was insufficient information to assess whether the other LABAs were equivalent to olodaterol or each other.

Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease.

Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease.

Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma.

Asthma patients who continue to experience symptoms despite taking regular inhaled corticosteroids (ICS) represent a management challenge. Long-acting beta2-agonists (LABA) and anti-leukotrienes (LTRA) are two treatment options that could be considered as add-on therapy to ICS. To compare the safety and efficacy of adding LABA versus LTRA to the treatment regimen for children and adults with asthma who remain symptomatic in spite of regular treatment with ICS. We specifically wished to examine the relative impact of the two agents on asthma exacerbations, lung function, symptoms, quality of life, adverse health events and withdrawals. We searched the Cochrane Airways Group Specialised Register until December 2012. We consulted reference lists of all included studies and contacted pharmaceutical manufacturers to ask about other published or unpublished studies. We included randomised controlled trials (RCTs) conducted in adults or children with recurrent asthma that was treated with ICS along with a fixed dose of a LABA or an LTRA for a minimum of four weeks. Two review authors independently assessed the risk of bias of included studies and extracted data. We sought unpublished data and further details of study design when necessary. We included 18 RCTs (7208 participants), of which 16 recruited adults and adolescents (6872) and two recruited children six to 17 years of age (336) with asthma and significant reversibility to bronchodilator at baseline. Fourteen (79%) trials were of high methodological quality.The risk of exacerbations requiring systemic corticosteroids (primary outcome of the review) was significantly lower with the combination of LABA + ICS compared with LTRA + ICS-from 13% to 11% (eight studies, 5923 adults and 334 children; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.76 to 0.99; high-quality evidence). The number needed to treat for an additional beneficial outcome (NNTB) with LABA compared with LTRA to prevent one additional exacerbation over four to 102 weeks was 62 (95% CI 34 to 794). The choice of LTRA, the dose of ICS and the participants' age group did not significantly influence the magnitude of effect. Although results were inconclusive, the effect appeared stronger in trials that used a single device rather than two devices to administer ICS and LABA and in trials of less than 12 weeks' duration.The addition of LABA to ICS was associated with a statistically greater improvement from baseline in lung function, as well as in symptoms, rescue medication use and quality of life, although the latter effects were modest. LTRA was superior in the prevention of exercise-induced bronchospasm. More participants were satisfied with the combination of LABA + ICS than LTRA + ICS (three studies, 1625 adults; RR 1.12, 95% CI 1.04 to 1.20; moderate-quality evidence). The overall risk of withdrawal was significantly lower with LABA + ICS than with LTRA + ICS (13 studies, 6652 adults and 308 children; RR 0.84, 95% CI 0.74 to 0.96; moderate-quality evidence). Although the risk of overall adverse events was equivalent between the two groups, the risk of serious adverse events (SAE) approached statistical significance in disfavour of LABA compared with LTRA (nine studies, 5658 adults and 630 children; RR 1.33, 95% CI 0.99 to 1.79; P value 0.06; moderate-quality evidence), with no apparent impact of participants' age group.The following adverse events were reported, but no significant differences were demonstrated between groups: headache (11 studies, N = 6538); cardiovascular events (five studies, N = 5163), osteopenia and osteoporosis (two studies, N = 2963), adverse events (10 studies, N = 5977 adults and 300 children). A significant difference in the risk of oral moniliasis was noted, but this represents a low occurrence rate. In adults with asthma that is inadequately controlled by predominantly low-dose ICS with significant bronchodilator reversibility, the addition of LABA to ICS is modestly superior to the addition of LTRA in reducing oral corticosteroid-treated exacerbations, with an absolute reduction of two percentage points. Differences favouring LABA over LTRA as adjunct therapy were observed in lung function and, to a lesser extend, in rescue medication use, symptoms and quality of life. The lower overall withdrawal rate and the higher proportion of participants satisfied with their therapy indirectly favour the combination of LABA + ICS over LTRA + ICS. Evidence showed a slightly increased risk of SAE with LABA compared with LTRA, with an absolute increase of one percentage point. Our findings modestly support the use of a single inhaler for the delivery of both LABA and low- or medium-dose ICS. Because of the paucity of paediatric trials, we are unable to draw firm conclusions about the best adjunct therapy in children.

Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid

Asthma is a common respiratory disease among both adults and children and short acting inhaled beta-2 agonists are used widely for 'reliever' bronchodilator therapy. Long acting beta-2 agonists (LABA) were introduced as prospective 'symptom controllers' in addition to inhaled corticosteroid 'preventer' therapy (ICS). In this updated review we have included studies in which patients were either not on ICS as a group, or in which some patients, but not all, were on ICS to complement previous systematic reviews of studies where LABA was given in patients uniformly receiving ICS. We have focussed particularly on serious adverse events, given previous concerns about potential risks, especially of death, from regular beta-2 agonist use. This review aimed to determine the benefit or detriment on the primary outcome of asthma control with the regular use of LABA compared with placebo, in mixed populations in which only some were taking ICS and in populations not using ICS therapy. We carried out searches using the Cochrane Airways Group trial register, most recently in October 2005. We searched bibliographies of identified RCTs for additional relevant RCTs and contacted authors of identified RCTs for other published and unpublished studies. All randomised studies of at least four weeks duration, comparing a LABA given twice daily with a placebo, in chronic asthma. Selection criteria to this updated review have been altered to accommodate recently published Cochrane reviews on combination and addition of LABA to ICS therapy. Studies in which all individuals were uniformly taking ICS were excluded from this review. Two reviewers performed data extraction and study quality assessment independently. We contacted authors of studies for missing data. Sixty-seven studies (representing 68 experimental comparisons) randomising 42,333 participants met the inclusion criteria. Salmeterol was used as long-acting agent in 50 studies and formoterol fumarate in 17. The treatment period was four to nine weeks in 29 studies, and 12 to 52 weeks in 38 studies. Twenty-four studies did not permit the use of ICS, and forty permitted either inhaled corticosteroid or cromones (in three studies this was unclear). In these studies between 22% and 92% were taking ICS, with a median of 62%. There were significant advantages to LABA treatment compared to placebo for a variety of measurements of airway calibre including morning peak expiratory flow (PEF), evening PEF and FEV1. They were associated with significantly fewer symptoms, less use of rescue medication and higher quality of life scores. This was true whether patients were taking LABA in combination with ICS or not. Findings from SMART (a recently published surveillance study) indicated significant increases in asthma related deaths, respiratory related deaths and combined asthma related deaths and life threatening experiences. The absolute increase in asthma-related mortality was consistent with an increase of around one per 1250 patients treated with LABA for six months, but the confidence intervals are wide (from 700 to 10,000). Post-hoc exploratory subgroups suggested that African-Americans and those not on inhaled corticosteroids were at particular risk for the primary end-point of death or life-threatening asthma event. There was also a suggestion of an increase in exacerbation rate in children. Pharmacologically predicted side effects such as headache, throat irritation, tremor and nervousness were more frequent with LABA treatment. LABA are effective in the control of chronic asthma in the "real-life" subject groups included. However there are potential safety issues which call into question the safety of LABA, particularly in those asthmatics who are not taking ICS, and it is not clear why African-Americans were found to have significant differences in comparison to Caucasians for combined respiratory-related death and life threatening experiences, but not for asthma-related death.

Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study

The contributions of as-needed inhaled corticosteroids and long-acting beta2 agonists (LABA) to asthma control have not been fully established. We compared the efficacy and safety of three reliever strategies: a traditional short-acting beta2 agonist; a rapid-onset LABA (formoterol); and a combination of LABA and an inhaled corticosteroid (budesonide-formoterol) in symptomatic patients receiving budesonide-formoterol maintenance therapy. We did a 12-month, double-blind, parallel-group study in 3394 patients (aged 12 years or older), in 289 centres in 20 countries, who were using inhaled corticosteroids at study entry and symptomatic on budesonide-formoterol (160 microg and 4.5 microg, respectively), one inhalation twice daily, during a 2-week run-in. After run-in, patients were randomly assigned budesonide-formoterol maintenance therapy plus one of three alternative as-needed medications-terbutaline (0.4 mg), formoterol (4.5 microg), or budesonide-formoterol (160 microg and 4.5 microg). The primary outcome was time to first severe exacerbation, defined as an event resulting in hospitalisation, emergency room treatment, or both, or the need for oral steroids for 3 days or more. Time to first severe exacerbation was longer with as-needed budesonide-formoterol versus formoterol (p=0.0048; log-rank test) and with as-needed formoterol versus terbutaline (p=0.0051). The rate of severe exacerbations was 37, 29, and 19 per 100 patients per year with as-needed terbutaline, formoterol, and budesonide-formoterol, respectively (rate ratios budesonide-formoterol versus formoterol 0.67 [95% CI 0.56-0.80; p<0.0001]; budesonide-formoterol versus terbutaline 0.52 [0.44-0.62; p<0.0001]; formoterol versus terbutaline 0.78 [0.67-0.91; p=0.0012]). Asthma control days increased to a similar extent in all treatment groups. As-needed formoterol did not significantly improve symptoms compared with as-needed terbutaline. All treatments were well tolerated. Both monocomponents of budesonide-formoterol given as needed contribute to enhanced protection from severe exacerbations in patients receiving combination therapy for maintenance.