Comparative data on the efficacies of long-acting muscarinic antagonist (LAMA) and long-acting β
-agonist (LABA) combinations for the treatment of moderate-to-very-severe chronic obstructive ...pulmonary disease (COPD) are limited. The aim of this Bayesian network meta-analysis (NMA) is to assess the relative efficacies of available open combinations (delivered via separate inhalers) and fixed-dose combinations (FDCs, delivered via a single inhaler).
We conducted a systematic literature review with the aim of identifying randomized controlled trials (RCTs) of ≥8-week duration in adults aged ≥40 years with COPD that compared LAMA + LABA combinations with each other, with tiotropium (TIO), or with placebo. Data on changes from baseline in trough forced expiratory volume in 1 s (FEV
) and on St George's Respiratory Questionnaire (SGRQ) total score, the Transition Dyspnea Index (TDI) focal score, and rescue medication use at 12 and 24 weeks were extracted from these RCTs and analyzed using a NMA in a Bayesian framework.
Data from 44 RCTs were included in the NMA. All FDCs showed improvements relative to placebo in terms of trough FEV
, SGRQ total score, and TDI focal score above clinically relevant thresholds, with the exception of TIO/olodaterol and aclidinium/formoterol, both of which failed to show clinically relevant improvements in SGRQ score at 24 weeks. All FDCs demonstrated reduced rescue medication use versus placebo. Open combinations demonstrated improved efficacy in all outcomes versus placebo, but these improvements did not consistently exceed clinically relevant thresholds for SGRQ and TDI scores. All once-daily FDCs showed improved efficacy versus TIO, but improvements were less consistently observed versus TIO with open dual combinations and combinations containing formoterol or salmeterol administered twice daily. Relative probabilities of improvement between FDCs highlighted potential between-class differences for trough FEV
but suggested little potential for differences in patient-reported outcomes.
LAMA + LABA combinations generally showed improved outcomes versus placebo and TIO. FDCs appeared to perform better than open dual combinations. A potential effectiveness gradient was observed between FDCs for objectively assessed functional outcomes, although further prospective trials are required to confirm these findings.
GSK.
Background: Airway obstruction induced by physical exercise is a common feature in asthma, and conventional treatments do not offer optimal protection. There is thus a need for additional therapies ...for optimal control of exercise-induced bronchoconstriction (EIB). Objective: The influence of treatment with the antihistamine loratadine and the antileukotriene zafirlukast alone and in combination on EIB was investigated. This combination has previously shown beneficial additive effects in allergen-induced bronchoconstriction. Methods: In a double-blind cross-over study loratadine (10 mg twice daily) and zafirlukast (80 mg twice daily) were evaluated alone and in combination in 16 nonsmoking patients with mild asthma, previously documented EIB, and airways hyperresponsiveness to histamine. Results: The mean ± SE maximum decrease in FEV1 after a standardized exercise provocation was 21.6% ± 3% after placebo, 22.8% ± 3% after loratadine, 13.9% ± 2% after zafirlukast (P < .05 vs placebo), and 10.3% ± 2% after the combination of loratadine and zafirlukast (P < .05 vs placebo). Expressed as the area under the FEV1 percentage change versus time curve, the mean protection produced by zafirlukast and the combination of zafirlukast and loratadine was 57% and 65%, respectively, whereas loratadine alone had no significant protective effect. There was also no significant difference between the effect of zafirlukast alone or in combination with loratadine. Conclusion: The study confirmed the beneficial effect of a leukotriene receptor antagonist in EIB but failed to obtain evidence that H1-receptor antagonism alone or together with the cysteinyl-leukotriene 1 receptor antagonist zafirlukast offers a protective effect. (J Allergy Clin Immunol 2002;109:789-93.)
Background: In chronic obstructive pulmonary disease (COPD), both the time needed for patients to gain symptom improvement with long-acting bronchodilator therapy and whether an early response is ...predictive of a sustained response is unknown. This study aimed to investigate how quickly meaningful symptom responses are seen in patients with COPD with bronchodilator therapy and whether these responses are sustained. Methods: Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a 24-week, double-blind, double-dummy, parallel-group trial that randomised patients to umeclidinium/vilanterol (UMEC/VI), umeclidinium or salmeterol. Daily Evaluating Respiratory Symptoms in COPD (E-RS:COPD) score and rescue salbutamol use were captured via an electronic diary and analysed initially in 4-weekly periods. Post hoc analyses assessed change from baseline in daily E-RS:COPD score and rescue medication use weekly (Weeks 1–8), and association between E-RS:COPD responder status at Weeks 1–4 and later time points. Results: In the intent-to-treat population ( n = 2425), reductions from baseline in E-RS:COPD scores and rescue medication use were apparent from Day 2 with all treatments. Treatment differences for UMEC/VI versus either monotherapy plateaued by Week 4–8 and were sustained at Weeks 21–24; improvements were consistently greater with UMEC/VI. For all treatments, most patients (60–85%) retained their Weeks 1–4 E-RS:COPD responder/non-responder status at Weeks 21−24. Among patients receiving UMEC/VI who were E-RS:COPD responders at Weeks 1–4, 70% were responders at Weeks 21–24. Conclusion: Patients with symptomatic COPD had greater potential for early symptom improvements with UMEC/VI versus either monotherapy. This benefit was generally maintained for 24 weeks. Early monitoring of treatment response can provide clinicians with an early indication of a patient’s likely longer-term response to prescribed bronchodilator treatment and will facilitate appropriate early adjustments in care. Clinical Trial Registration: NCT03034915, 2016-002513-22 (EudraCT Number). The reviews of this paper are available via the supplemental material section.
Rationale: Symptom relief is a key treatment goal in patients with chronic obstructive pulmonary disease (COPD). However, there are limited data available on the response to bronchodilator therapy in ...patients at low risk of exacerbations with different levels of symptom severity. This study compared treatment responses in patients with a range of symptom severities as indicated by baseline COPD assessment test (CAT) scores. Methods: The 24-week EMAX trial evaluated the benefits of umeclidinium/vilanterol versus umeclidinium or salmeterol in symptomatic patients at low exacerbation risk who were not receiving inhaled corticosteroids. This analysis assessed lung function, symptoms, health status, and short-term deterioration outcomes in subgroups defined by a baseline CAT score <20 ( post hoc ) and ⩾20 (pre-specified). Outcomes were also assessed using post hoc fractional polynomial modelling with continuous transformations of baseline CAT score covariates. Results: Of the intent-to-treat population ( n = 2425), 56% and 44% had baseline CAT scores of <20 and ⩾20, respectively. Umeclidinium/vilanterol demonstrated favourable improvements compared with umeclidinium and salmeterol for the majority of outcomes irrespective of the baseline CAT score, with the greatest improvements generally observed in patients with CAT scores <20. Fractional polynomial analyses revealed consistent improvements in lung function, symptoms and reduction in rescue medication use with umeclidinium/vilanterol versus umeclidinium and salmeterol across a range of CAT scores, with the largest benefits seen in patients with CAT scores of approximately 10–21. Conclusions: Patients with symptomatic COPD benefit similarly from dual bronchodilator treatment with umeclidinium/vilanterol. Fractional polynomial analyses demonstrated the greatest treatment differences favouring dual therapy in patients with a CAT score <20, although benefits were seen up to scores of 30. This suggests that dual bronchodilation may be considered as initial therapy for patients across a broad range of symptom severities, not only those with severe symptoms (CAT ⩾20). Trial registration: NCT03034915, 2016-002513-22 (EudraCT number). The reviews of this paper are available via the supplemental material section.
The study objective was to assess whether asthmatic adolescents who were regular users of inhaled corticosteroids preferred treatment with zafirlukast tablets or inhaled beclomethasone dipropionate ...(BDP), and, secondarily, to assess adolescents’ inhaler technique and their opinions about treatment. An open‐label, randomized, two‐period, cross‐over study was conducted in 18 centres (primary care to specialist asthma centres) in South Africa, the UK, Finland and the Czech Republic. One hundred and thirty‐two adolescents aged 12–17 years with asthma for at least 1 year and FEV1 ≥ 75% of predicted, treated with short‐acting bronchodilators and inhaled corticosteroids, entered the study. Patients received oral zafirlukast tablets (Accolate™) 20 mg bd or inhaled BDP 100 or 200 µg bd, provided by a standard pressurized metered‐dose inhaler, for 4 weeks each. One questionnaire was used to determine preference (the primary outcome measure) and a second questionnaire was used to determine patients’ likes and dislikes of treatment. Investigators also scored inhaler technique. Of 113 adolescents, 79 (70%) preferred zafirlukast compared with 31 (27%) who preferred the BDP inhaler (p < 0.001); three had no preference. Only 35 (29%) of 122 adolescents could use their inhaler correctly at study entry. Seventy‐six patients (65%) rated zafirlukast tablets as ‘very easy’ to use, compared with 35 (30%) for the BDP inhaler. Both treatments were well tolerated. This study shows that asthmatic adolescents prefer zafirlukast tablets by a ratio of 2.6:1 over inhaled BDP, and these results may have implications for improving adolescent patient compliance with asthma therapy.
Background: Single doses of zafirlukast attenuate exercise-induced bronchoconstriction (EIB), but previous studies have not measured zafirlukast’s effects after regular dosing or its duration of ...effect beyond 4 hours.
Objective: The purpose of this study was to assess the effects of zafirlukast 20 mg and 80 mg twice daily compared with placebo on exercise challenges performed at 2 and 8 hours after the last dose of regular administration.
Methods: Twenty-four adult patients with stable asthma taking β
2-agonists, inhaled corticosteroids, or both received treatment with zafirlukast (20 mg and 80 mg) and placebo. The patients were treated twice daily for 14 days in a randomized, double-blind, 3-way cross-over fashion, with a 7-day washout period between each treatment. Exercise challenges were performed at 2 and 8 hours after the morning dose on day 14. FEV
1 was measured before exercise and at set intervals after exercise until it returned to within 7% of its baseline value.
Results: Both zafirlukast treatments significantly reduced EIB, as measured by the area under the FEV
1 time curve after the 2-hour (
P < .001) and 8-hour (
P < .001) exercise challenges and maximum fall in FEV
1 at the 2-hour challenge (
P < .001). The comparison at 8 hours between treatments was affected by the unexpected finding that EIB was less in the placebo group after the 8-hour challenge than after the 2-hour challenge, as measured by the within-group change in the maximum fall in FEV
1 (
P < .001) and the area under the FEV
1 time curve (
P = .0023).
Conclusion: Regular zafirlukast treatment protects against EIB for at least 8 hours after regular dosing. A refractory period, which may be caused by exercise-induced leukotriene release, may last for up to 6 hours after the initial response to exercise. (J Allergy Clin Immunol 1999;1155-61.)
Background:
Combination therapy with inhaled corticosteroids (ICSs) and long-acting β 2 -agonists (LABAs), or treatment with high doses of ICSs alone improves asthma control when therapy with ...low-dose ICSs is not
sufficient. However, it is not known which of these treatment options is more effective in sustaining asthma control.
Objectives:
To evaluate the effect of increasing the ICS dosage vs adding LABAs on the time spent with well-controlled asthma or poorly
controlled asthma.
Methods:
Post hoc analysis of the Formoterol and Corticosteroid Establishing Therapy study, which compared a fourfold increase in the budesonide
dose with and without formoterol.
Results:
Time with well-controlled asthma was improved by 19% (95% confidence interval CI, 3 to 35%; p = 0.017) by adding formoterol,
24 μg/d, to therapy with budesonide, 200 μg/d, compared to 2% (95% CI, â9 to 12%; p = 0.76) with therapy with budesonide,
800 μg/d, alone. Time with well-controlled asthma was further improved by 29% (95% CI, 13 to 47%; p < 0.001) by adding formoterol
to therapy with budesonide, 800 μg/d. Time with poorly controlled asthma was significantly reduced using the same interventions
by 43% (95% CI, 25 to 57%), 22% (95% CI, 7 to 44%), and 50% (95% CI, 30 to 64%), respectively. Adding formoterol to budesonide
was significantly more effective in increasing time with well-controlled asthma when compared to increasing the budesonide
dose fourfold (increase, 16%; 95% CI, 1 to 33%; p = 0.035), with a trend for a greater reduction in time with poor control
(decrease, 21%; 95% CI, â5 to 42%).
Conclusion:
The addition of formoterol to therapy with low-dose budesonide increases the probability of well-controlled asthma compared
to a substantial increase in the dose of an ICS.
asthma control
budesonide
formoterol
inhaled corticosteroids
long-acting β2-agonists
Combination therapy with inhaled corticosteroids (ICSs) and long-acting beta(2)-agonists (LABAs), or treatment with high doses of ICSs alone improves asthma control when therapy with low-dose ICSs is ...not sufficient. However, it is not known which of these treatment options is more effective in sustaining asthma control.
To evaluate the effect of increasing the ICS dosage vs adding LABAs on the time spent with well-controlled asthma or poorly controlled asthma.
Post hoc analysis of the Formoterol and Corticosteroid Establishing Therapy study, which compared a fourfold increase in the budesonide dose with and without formoterol.
Time with well-controlled asthma was improved by 19% (95% confidence interval CI, 3 to 35%; p = 0.017) by adding formoterol, 24 microg/d, to therapy with budesonide, 200 microg/d, compared to 2% (95% CI, -9 to 12%; p = 0.76) with therapy with budesonide, 800 microg/d, alone. Time with well-controlled asthma was further improved by 29% (95% CI, 13 to 47%; p < 0.001) by adding formoterol to therapy with budesonide, 800 microg/d. Time with poorly controlled asthma was significantly reduced using the same interventions by 43% (95% CI, 25 to 57%), 22% (95% CI, 7 to 44%), and 50% (95% CI, 30 to 64%), respectively. Adding formoterol to budesonide was significantly more effective in increasing time with well-controlled asthma when compared to increasing the budesonide dose fourfold (increase, 16%; 95% CI, 1 to 33%; p = 0.035), with a trend for a greater reduction in time with poor control (decrease, 21%; 95% CI, -5 to 42%).
The addition of formoterol to therapy with low-dose budesonide increases the probability of well-controlled asthma compared to a substantial increase in the dose of an ICS.
PDF
