-
JAMA Jun 2021The benefits and harms of adding long-acting muscarinic antagonists (LAMAs) to inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs) for moderate to severe... (Comparative Study)
Comparative Study Meta-Analysis
IMPORTANCE
The benefits and harms of adding long-acting muscarinic antagonists (LAMAs) to inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs) for moderate to severe asthma remain unclear.
OBJECTIVE
To systematically synthesize the outcomes and adverse events associated with triple therapy (ICS, LABA, and LAMA) vs dual therapy (ICS plus LABA) in children and adults with persistent uncontrolled asthma.
DATA SOURCES
MEDLINE, Embase, CENTRAL, ICTRP, FDA, and EMA databases from November 2017, to December 8, 2020, without language restriction.
STUDY SELECTION
Two investigators independently selected randomized clinical trials (RCTs) comparing triple vs dual therapy in patients with moderate to severe asthma.
DATA EXTRACTION AND SYNTHESIS
Two reviewers independently extracted data and assessed risk of bias. Random-effects meta-analyses, including individual patient-level exacerbation data, were used. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach was used to assess certainty (quality) of the evidence.
MAIN OUTCOMES AND MEASURES
Severe exacerbations, asthma control (measured using the Asthma Control Questionnaire [ACQ-7], a 7-item list with each item ranging from 0 [totally controlled] to 6 [severely uncontrolled]; minimal important difference, 0.5), quality of life (measured using the Asthma-related Quality of Life [AQLQ] tool; score range, 1 [severely impaired] to 7 [no impairment]; minimal important difference, 0.5), mortality, and adverse events.
RESULTS
Twenty RCTs using 3 LAMA types that enrolled 11 894 children and adults (mean age, 52 years [range, 9-71 years]; 57.7% female) were included. High-certainty evidence showed that triple therapy vs dual therapy was significantly associated with a reduction in severe exacerbation risk (9 trials [9932 patients]; 22.7% vs 27.4%; risk ratio, 0.83 [95% CI, 0.77 to 0.90]) and an improvement in asthma control (14 trials [11 230 patients]; standardized mean difference [SMD], -0.06 [95% CI, -0.10 to -0.02]; mean difference in ACQ-7 scale, -0.04 [95% CI, -0.07 to -0.01]). There were no significant differences in asthma-related quality of life (7 trials [5247 patients]; SMD, 0.05 [95% CI, -0.03 to 0.13]; mean difference in AQLQ score, 0.05 [95% CI, -0.03 to 0.13]; moderate-certainty evidence) or mortality (17 trials [11 595 patients]; 0.12% vs 0.12%; risk ratio, 0.96 [95% CI, 0.33 to 2.75]; high-certainty evidence) between dual and triple therapy. Triple therapy was significantly associated with increased dry mouth and dysphonia (10 trials [7395 patients]; 3.0% vs 1.8%; risk ratio, 1.65 [95% CI, 1.14 to 2.38]; high-certainty evidence), but treatment-related and serious adverse events were not significantly different between groups (moderate-certainty evidence).
CONCLUSIONS AND RELEVANCE
Among children (aged 6 to 18 years) and adults with moderate to severe asthma, triple therapy, compared with dual therapy, was significantly associated with fewer severe asthma exacerbations and modest improvements in asthma control without significant differences in quality of life or mortality.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Anti-Asthmatic Agents; Asthma; Child; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Nebulizers and Vaporizers; Quality of Life; Severity of Illness Index; Symptom Flare Up; Xerostomia
PubMed: 34009257
DOI: 10.1001/jama.2021.7872 -
Allergy Apr 2022A significant number of patients with asthma remain uncontrolled despite treatment with inhaled corticosteroids (ICS) and long-acting β2 adrenergic bronchodilators... (Review)
Review
A significant number of patients with asthma remain uncontrolled despite treatment with inhaled corticosteroids (ICS) and long-acting β2 adrenergic bronchodilators (LABA). The addition of long-acting antimuscarinic agents (LAMA) can improve the management of asthma in these patients. Recently, three novel triple therapy (ICS/LABA/LAMA) formulations in a single-inhaler device (SITT) have been investigated in patients with uncontrolled asthma despite ICS/LABA treatment. Here, we review systematically the evidence available to date in relation to SITT in patients with uncontrolled asthma despite ICS-LABA treatment and conclude that SITT is a safe and effective therapeutic alternative in these patients. We also discuss how to position this new therapeutic alternative in their practical clinical management as well as the opportunities and challenges that it may generate for patients, physicians, and payers.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Asthma; Bronchodilator Agents; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive
PubMed: 34478578
DOI: 10.1111/all.15076 -
Advances in Therapy Nov 2021In the absence of head-to-head trials, we performed an indirect treatment comparison of the β-adrenergic agonists vibegron and mirabegron in the treatment of overactive...
BACKGROUND
In the absence of head-to-head trials, we performed an indirect treatment comparison of the β-adrenergic agonists vibegron and mirabegron in the treatment of overactive bladder (OAB).
METHODS
PubMed, Embase, and Cochrane Library were searched for articles related to phase 3, double-blind, controlled trials of vibegron 75 mg and mirabegron 25/50 mg in patients with OAB. Efficacy outcomes included change from baseline at weeks 4, 12, and 52 in mean daily number of total urinary incontinence episodes and micturitions and mean volume voided/micturition. Effect size was computed as placebo-subtracted change from baseline (weeks 4, 12) or active control (tolterodine)-subtracted change from baseline (week 52) for each treatment group. Adverse events (AEs) are presented descriptively.
RESULTS
After removal of duplicates, 49 records were identified, and after screening 9 met inclusion criteria for analysis. Vibegron showed significantly greater reduction in mean daily number of total incontinence episodes than mirabegron 25 mg at week 4, mirabegron 50 mg (weeks 4, 52), and tolterodine (weeks 4, 12) (P < 0.05, each) and significantly greater improvement in volume voided versus mirabegron 25 mg (week 12), mirabegron 50 mg (weeks 12, 52), and tolterodine (week 4) (P < 0.05, each). Confidence intervals of point estimates overlapped zero for all other comparisons of vibegron and mirabegron (25 or 50 mg) or tolterodine, indicating no significant differences between treatments for these time/endpoints. Urinary tract infection, hypertension, and dry mouth were the most commonly occurring AEs for vibegron, mirabegron, and tolterodine, respectively, in the short-term trials; hypertension was the most commonly occurring AE with all three treatments in the long-term trials.
CONCLUSIONS
Vibegron was associated with significant improvement in total incontinence episodes versus mirabegron at 4 and 52 weeks and volume voided at 12 and 52 weeks. Improvement in micturitions was similar between vibegron and mirabegron or tolterodine. Incidence of AEs was generally comparable between vibegron and mirabegron.
Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Clinical Trials, Phase III as Topic; Double-Blind Method; Humans; Muscarinic Antagonists; Pyrimidinones; Pyrrolidines; Randomized Controlled Trials as Topic; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive
PubMed: 34537953
DOI: 10.1007/s12325-021-01902-8 -
British Journal of Anaesthesia Dec 2019Dexmedetomidine (DEX) is a highly selective alpha2 adrenoceptor agonist with broad pharmacological effects, including sedation, analgesia, anxiolysis, and sympathetic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dexmedetomidine (DEX) is a highly selective alpha2 adrenoceptor agonist with broad pharmacological effects, including sedation, analgesia, anxiolysis, and sympathetic tone inhibition. Here we report a systematic review and meta-analysis of its effects on stress, inflammation, and immunity in surgical patients during the perioperative period.
METHODS
We searched MEDLINE, METSTR, Embase, and Web of Science for clinical studies or trials to analyse the effects of DEX on perioperative stress, inflammation, and immune function.
RESULTS
Sixty-seven studies (including randomised controlled trials and eight cohort studies) with 4842 patients were assessed, of which 2454 patients were in DEX groups and 2388 patients were in control (without DEX) groups. DEX infusion during the perioperative period inhibited release of epinephrine, norepinephrine, and cortisol; decreased blood glucose, interleukin (IL)-6, tumour necrosis factor-α, and C-reactive protein; and increased interleukin-10 in surgical patients. In addition, the numbers of natural killer cells, B cells, and CD4 T cells, and the ratios of CD4:CD8 and Th1:Th2 were significantly increased; CD8 T-cells were decreased in the DEX group when compared with the control group.
CONCLUSIONS
DEX, an anaesthesia adjuvant, can attenuate perioperative stress and inflammation, and protect the immune function of surgical patients, all of which may contribute to decreased postoperative complications and improved clinical outcomes.
Topics: Adrenergic alpha-2 Receptor Agonists; Dexmedetomidine; Humans; Immunity; Inflammation; Intraoperative Complications; Postoperative Complications; Preoperative Period; Stress, Physiological
PubMed: 31668347
DOI: 10.1016/j.bja.2019.07.027 -
The Cochrane Database of Systematic... Aug 2022Preterm birth is the leading cause of death in newborns and children. Tocolytic drugs aim to delay preterm birth by suppressing uterine contractions to allow time for... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Preterm birth is the leading cause of death in newborns and children. Tocolytic drugs aim to delay preterm birth by suppressing uterine contractions to allow time for administration of corticosteroids for fetal lung maturation, magnesium sulphate for neuroprotection, and transport to a facility with appropriate neonatal care facilities. However, there is still uncertainty about their effectiveness and safety.
OBJECTIVES
To estimate relative effectiveness and safety profiles for different classes of tocolytic drugs for delaying preterm birth, and provide rankings of the available drugs.
SEARCH METHODS
We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov (21 April 2021) and reference lists of retrieved studies.
SELECTION CRITERIA
We included all randomised controlled trials assessing effectiveness or adverse effects of tocolytic drugs for delaying preterm birth. We excluded quasi- and non-randomised trials. We evaluated all studies against predefined criteria to judge their trustworthiness.
DATA COLLECTION AND ANALYSIS
At least two review authors independently assessed the trials for inclusion and risk of bias, and extracted data. We performed pairwise and network meta-analyses, to determine the relative effects and rankings of all available tocolytics. We used GRADE to rate the certainty of the network meta-analysis effect estimates for each tocolytic versus placebo or no treatment.
MAIN RESULTS
This network meta-analysis includes 122 trials (13,697 women) involving six tocolytic classes, combinations of tocolytics, and placebo or no treatment. Most trials included women with threatened preterm birth, singleton pregnancy, from 24 to 34 weeks of gestation. We judged 25 (20%) studies to be at low risk of bias. Overall, certainty in the evidence varied. Relative effects from network meta-analysis suggested that all tocolytics are probably effective in delaying preterm birth compared with placebo or no tocolytic treatment. Betamimetics are possibly effective in delaying preterm birth by 48 hours (risk ratio (RR) 1.12, 95% confidence interval (CI) 1.05 to 1.20; low-certainty evidence), and 7 days (RR 1.14, 95% CI 1.03 to 1.25; low-certainty evidence). COX inhibitors are possibly effective in delaying preterm birth by 48 hours (RR 1.11, 95% CI 1.01 to 1.23; low-certainty evidence). Calcium channel blockers are possibly effective in delaying preterm birth by 48 hours (RR 1.16, 95% CI 1.07 to 1.24; low-certainty evidence), probably effective in delaying preterm birth by 7 days (RR 1.15, 95% CI 1.04 to 1.27; moderate-certainty evidence), and prolong pregnancy by 5 days (0.1 more to 9.2 more; high-certainty evidence). Magnesium sulphate is probably effective in delaying preterm birth by 48 hours (RR 1.12, 95% CI 1.02 to 1.23; moderate-certainty evidence). Oxytocin receptor antagonists are probably effective in delaying preterm birth by 48 hours (RR 1.13, 95% CI 1.05 to 1.22; moderate-certainty evidence), are effective in delaying preterm birth by 7 days (RR 1.18, 95% CI 1.07 to 1.30; high-certainty evidence), and possibly prolong pregnancy by 10 days (95% CI 2.3 more to 16.7 more). Nitric oxide donors are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.05 to 1.31; moderate-certainty evidence), and 7 days (RR 1.18, 95% CI 1.02 to 1.37; moderate-certainty evidence). Combinations of tocolytics are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.07 to 1.27; moderate-certainty evidence), and 7 days (RR 1.19, 95% CI 1.05 to 1.34; moderate-certainty evidence). Nitric oxide donors ranked highest for delaying preterm birth by 48 hours and 7 days, and delay in birth (continuous outcome), followed by calcium channel blockers, oxytocin receptor antagonists and combinations of tocolytics. Betamimetics (RR 14.4, 95% CI 6.11 to 34.1; moderate-certainty evidence), calcium channel blockers (RR 2.96, 95% CI 1.23 to 7.11; moderate-certainty evidence), magnesium sulphate (RR 3.90, 95% CI 1.09 to 13.93; moderate-certainty evidence) and combinations of tocolytics (RR 6.87, 95% CI 2.08 to 22.7; low-certainty evidence) are probably more likely to result in cessation of treatment. Calcium channel blockers possibly reduce the risk of neurodevelopmental morbidity (RR 0.51, 95% CI 0.30 to 0.85; low-certainty evidence), and respiratory morbidity (RR 0.68, 95% CI 0.53 to 0.88; low-certainty evidence), and result in fewer neonates with birthweight less than 2000 g (RR 0.49, 95% CI 0.28 to 0.87; low-certainty evidence). Nitric oxide donors possibly result in neonates with higher birthweight (mean difference (MD) 425.53 g more, 95% CI 224.32 more to 626.74 more; low-certainty evidence), fewer neonates with birthweight less than 2500 g (RR 0.40, 95% CI 0.24 to 0.69; low-certainty evidence), and more advanced gestational age (MD 1.35 weeks more, 95% CI 0.37 more to 2.32 more; low-certainty evidence). Combinations of tocolytics possibly result in fewer neonates with birthweight less than 2500 g (RR 0.74, 95% CI 0.59 to 0.93; low-certainty evidence). In terms of maternal adverse effects, betamimetics probably cause dyspnoea (RR 12.09, 95% CI 4.66 to 31.39; moderate-certainty evidence), palpitations (RR 7.39, 95% CI 3.83 to 14.24; moderate-certainty evidence), vomiting (RR 1.91, 95% CI 1.25 to 2.91; moderate-certainty evidence), possibly headache (RR 1.91, 95% CI 1.07 to 3.42; low-certainty evidence) and tachycardia (RR 3.01, 95% CI 1.17 to 7.71; low-certainty evidence) compared with placebo or no treatment. COX inhibitors possibly cause vomiting (RR 2.54, 95% CI 1.18 to 5.48; low-certainty evidence). Calcium channel blockers (RR 2.59, 95% CI 1.39 to 4.83; low-certainty evidence), and nitric oxide donors probably cause headache (RR 4.20, 95% CI 2.13 to 8.25; moderate-certainty evidence).
AUTHORS' CONCLUSIONS
Compared with placebo or no tocolytic treatment, all tocolytic drug classes that we assessed (betamimetics, calcium channel blockers, magnesium sulphate, oxytocin receptor antagonists, nitric oxide donors) and their combinations were probably or possibly effective in delaying preterm birth for 48 hours, and 7 days. Tocolytic drugs were associated with a range of adverse effects (from minor to potentially severe) compared with placebo or no tocolytic treatment, although betamimetics and combination tocolytics were more likely to result in cessation of treatment. The effects of tocolytic use on neonatal outcomes such as neonatal and perinatal mortality, and on safety outcomes such as maternal and neonatal infection were uncertain.
Topics: Adrenergic beta-Agonists; Birth Weight; Calcium Channel Blockers; Child; Female; Headache; Humans; Infant, Newborn; Magnesium Sulfate; Network Meta-Analysis; Nitric Oxide Donors; Pregnancy; Premature Birth; Randomized Controlled Trials as Topic; Receptors, Oxytocin; Tocolytic Agents; Vomiting
PubMed: 35947046
DOI: 10.1002/14651858.CD014978.pub2 -
Advances in Therapy Jun 2021In patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations or symptoms, despite being prescribed dual long-acting muscarinic... (Meta-Analysis)
Meta-Analysis
In patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations or symptoms, despite being prescribed dual long-acting muscarinic antagonist (LAMA)/long-acting β-agonist (LABA) or inhaled corticosteroid (ICS)/LABA therapies, triple ICS/LAMA/LABA therapy is recommended. A previous network meta-analysis showed comparable efficacy of the ICS/LAMA/LABA, budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR) 320/18/9.6 µg, to other fixed-dose and open combination triple therapies at 24 weeks in COPD. Subsequently, the ETHOS study was published, including data for 8509 patients, assessing the efficacy and safety of BUD/GLY/FOR over 52 weeks. This network meta-analysis (NMA) was conducted to compare the relative efficacy, safety, and tolerability of BUD/GLY/FOR 320/18/9.6 µg with other fixed-dose and open combination triple therapies in COPD over 52 weeks, including data from ETHOS. A systematic literature review was conducted to identify ≥ 10-week randomized controlled trials, including ≥ 1 fixed-dose or open combination triple-therapy arm, in patients with moderate-to-very severe COPD. The methodologic quality and risk of bias of included studies were assessed. Study results were combined using a three-level hierarchical Bayesian NMA model to assess efficacy and safety outcomes at or over 24 and 52 weeks. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. Nineteen studies (n = 37,741 patients) met the inclusion criteria of the review; 15 contributed to the base case network. LAMA/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes for exacerbations, lung function, symptoms, health-related quality of life, safety, and tolerability, the efficacy and safety of BUD/GLY/FOR were comparable to those of other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium bromide/formoterol fumarate) and open combinations at or over 24 and 52 weeks. Sensitivity analyses and meta-regression results for exacerbation outcomes were broadly in line with the base case NMA. In this NMA, BUD/GLY/FOR 320/18/9.6 μg showed comparable efficacy versus other ICS/LAMA/LABA fixed-dose or open combination therapies in terms of reducing exacerbation rates and improving lung function, symptoms and health-related quality of life in patients with moderate-to-very-severe COPD, in line with previously published meta-analysis results of triple combinations in COPD. The safety and tolerability profile of BUD/GLY/FOR was also found to be comparable to other triple combination therapies.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bayes Theorem; Bronchodilator Agents; Budesonide; Drug Combinations; Formoterol Fumarate; Fumarates; Glycopyrrolate; Humans; Muscarinic Antagonists; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Quality of Life
PubMed: 33929661
DOI: 10.1007/s12325-021-01703-z -
European Journal of Psychotraumatology 2021: Pharmacological approaches are widely used for post-traumatic stress disorder (PTSD) despite uncertainty over efficacy. : To determine the efficacy of all... (Meta-Analysis)
Meta-Analysis
: Pharmacological approaches are widely used for post-traumatic stress disorder (PTSD) despite uncertainty over efficacy. : To determine the efficacy of all pharmacological approaches, including monotherapy, augmentation and head-to-head approaches (drug versus drug, drug versus psychotherapy), in reducing PTSD symptom severity. : A systematic review and meta-analysis of randomised controlled trials were undertaken; 115 studies were included. : Selective serotonin reuptake inhibitors (SSRIs) were found to be statistically superior to placebo in reduction of PTSD symptoms but the effect size was small (standardised mean difference -0.28, 95% CI -0.39 to -0.17). For individual monotherapy agents compared to placebo in two or more studies, we found small statistically significant evidence for the antidepressants fluoxetine, paroxetine, sertraline, venlafaxine and the antipsychotic quetiapine. For pharmacological augmentation, we found small statistically significant evidence for prazosin and risperidone. : Some medications have a small positive effect on reducing PTSD symptom severity and can be considered as potential monotherapy treatments; these include fluoxetine, paroxetine, sertraline, venlafaxine and quetiapine. Two medications, prazosin and risperidone, also have a small positive effect when used to augment pharmacological monotherapy. There was no evidence of superiority for one intervention over another in the small number of head-to-head comparison studies.
Topics: Adrenergic alpha-1 Receptor Antagonists; Antipsychotic Agents; Drug Synergism; Drug Therapy, Combination; Humans; Selective Serotonin Reuptake Inhibitors; Stress Disorders, Post-Traumatic
PubMed: 34992738
DOI: 10.1080/20008198.2020.1802920 -
International Journal of Environmental... Dec 2022Nightmares are highly prevalent and distressing for the sufferer, which underlines the need for well-documented treatments. A comprehensive literature review and... (Meta-Analysis)
Meta-Analysis Review
Nightmares are highly prevalent and distressing for the sufferer, which underlines the need for well-documented treatments. A comprehensive literature review and meta-analysis of the effects of different pharmacological placebo-controlled randomized clinical trials, covering the period up to 1 December 2022, was performed. Searches were conducted in PubMed, Embase, Web of Science, PsychInfo, Cinahl, and Google Scholar, resulting in the identification of 1762 articles, of which 14 met the inclusion criteria: pharmacological intervention of nightmares, based on a placebo-controlled randomized trial published in a European language, reporting outcomes either/or in terms of nightmare frequency, nightmare distress, or nightmare intensity, and reporting sufficient information enabling calculation of effect sizes. Most studies involved the effect of the α-adrenergic antagonist prazosin in samples of veterans or soldiers suffering from posttraumatic stress disorder. Other medications used were hydroxyzine, clonazepam, cyproheptadine, nabilone, and doxazosin. The vast majority of studies were conducted in the USA. The studies comprised a total of 830 participants. The Clinician-Administered PTSD Scale was the most frequently used outcome measure. The results showed an overall effect size of Hedges' = 0.50 (0.42 after adjustment for publication bias). The synthetic cannabinoid nabilone (one study) showed the highest effect size ( = 1.86), followed by the histamine H-antagonist hydroxyzine (one study), and prazosin (10 studies), with effect sizes of = 1.17 and = 0.54, respectively. Findings and limitations are discussed, and recommendations for future studies are provided.
Topics: Humans; Dreams; Randomized Controlled Trials as Topic; Prazosin; Adrenergic alpha-1 Receptor Antagonists; Stress Disorders, Post-Traumatic; Hydroxyzine
PubMed: 36613097
DOI: 10.3390/ijerph20010777 -
Advances in Therapy Nov 2022Few randomised controlled trials (RCTs) have directly compared long-acting muscarinic antagonist/long-acting β-agonist (LAMA/LABA) dual maintenance therapies for... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Few randomised controlled trials (RCTs) have directly compared long-acting muscarinic antagonist/long-acting β-agonist (LAMA/LABA) dual maintenance therapies for patients with chronic obstructive pulmonary disease (COPD). This systematic literature review and network meta-analysis (NMA) compared the efficacy of umeclidinium/vilanterol (UMEC/VI) versus other dual and mono-bronchodilator therapies in symptomatic patients with COPD.
METHODS
A systematic literature review (October 2015-November 2020) was performed to identify RCTs ≥ 8 weeks long in adult patients with COPD that compared LAMA/LABA combinations against any long-acting bronchodilator-containing dual therapy or monotherapy. Data extracted on changes from baseline in trough forced expiratory volume in 1 s (FEV), St George's Respiratory Questionnaire (SGRQ) total score, Transitional Dyspnoea Index (TDI) focal score, rescue medication use and moderate/severe exacerbation rate were analysed using an NMA in a frequentist framework. The primary comparison was at 24 weeks. Fixed effects model results are presented.
RESULTS
The NMA included 69 full-length publications (including 10 GSK clinical study reports) reporting 49 studies. At 24 weeks, UMEC/VI provided statistically significant greater improvements in FEV versus all dual therapy and monotherapy comparators. UMEC/VI provided similar improvements in SGRQ total score compared with all other LAMA/LABAs, and significantly greater improvements versus UMEC 125 μg, glycopyrronium 50 μg, glycopyrronium 18 μg, tiotropium 18 μg and salmeterol 50 μg. UMEC/VI also provided significantly better outcomes versus some comparators for TDI focal score, rescue medication use, annualised moderate/severe exacerbation rate, and time to first moderate/severe exacerbation.
CONCLUSION
UMEC/VI provided generally better outcomes compared with LAMA or LABA monotherapies, and consistent improvements in lung function (measured by change from baseline in trough FEV at 24 weeks) versus dual therapies. Treatment with UMEC/VI may improve outcomes for symptomatic patients with COPD compared with alternative maintenance treatments.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adult; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Dyspnea; Forced Expiratory Volume; Glycopyrrolate; Humans; Muscarinic Antagonists; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome
PubMed: 35857184
DOI: 10.1007/s12325-022-02234-x -
The Cochrane Database of Systematic... May 2021Asthma affects 350 million people worldwide including 45% to 70% with mild disease. Treatment is mainly with inhalers containing beta₂-agonists, typically taken as... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Asthma affects 350 million people worldwide including 45% to 70% with mild disease. Treatment is mainly with inhalers containing beta₂-agonists, typically taken as required to relieve bronchospasm, and inhaled corticosteroids (ICS) as regular preventive therapy. Poor adherence to regular therapy is common and increases the risk of exacerbations, morbidity and mortality. Fixed-dose combination inhalers containing both a steroid and a fast-acting beta₂-agonist (FABA) in the same device simplify inhalers regimens and ensure symptomatic relief is accompanied by preventative therapy. Their use is established in moderate asthma, but they may also have potential utility in mild asthma.
OBJECTIVES
To evaluate the efficacy and safety of single combined (fast-onset beta₂-agonist plus an inhaled corticosteroid (ICS)) inhaler only used as needed in people with mild asthma.
SEARCH METHODS
We searched the Cochrane Airways Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase, ClinicalTrials.gov and the World Health Organization (WHO) trials portal. We contacted trial authors for further information and requested details regarding the possibility of unpublished trials. The most recent search was conducted on 19 March 2021.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and cross-over trials with at least one week washout period. We included studies of a single fixed-dose FABA/ICS inhaler used as required compared with no treatment, placebo, short-acting beta agonist (SABA) as required, regular ICS with SABA as required, regular fixed-dose combination ICS/long-acting beta agonist (LABA), or regular fixed-dose combination ICS/FABA with as required ICS/FABA. We planned to include cluster-randomised trials if the data had been or could be adjusted for clustering. We excluded trials shorter than 12 weeks. We included full texts, abstracts and unpublished data.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data. We analysed dichotomous data as odds ratios (OR) or rate ratios (RR) and continuous data as mean difference (MD). We reported 95% confidence intervals (CIs). We used Cochrane's standard methodological procedures of meta-analysis. We applied the GRADE approach to summarise results and to assess the overall certainty of evidence. Primary outcomes were exacerbations requiring systemic steroids, hospital admissions/emergency department or urgent care visits for asthma, and measures of asthma control.
MAIN RESULTS
We included six studies of which five contributed results to the meta-analyses. All five used budesonide 200 μg and formoterol 6 μg in a dry powder formulation as the combination inhaler. Comparator fast-acting bronchodilators included terbutaline and formoterol. Two studies included children aged 12+ and adults; two studies were open-label. A total of 9657 participants were included, with a mean age of 36 to 43 years. 2.3% to 11% were current smokers. FABA / ICS as required versus FABA as required Compared with as-required FABA alone, as-required FABA/ICS reduced exacerbations requiring systemic steroids (OR 0.45, 95% CI 0.34 to 0.60, 2 RCTs, 2997 participants, high-certainty evidence), equivalent to 109 people out of 1000 in the FABA alone group experiencing an exacerbation requiring systemic steroids, compared to 52 (95% CI 40 to 68) out of 1000 in the FABA/ICS as-required group. FABA/ICS as required may also reduce the odds of an asthma-related hospital admission or emergency department or urgent care visit (OR 0.35, 95% CI 0.20 to 0.60, 2 RCTs, 2997 participants, low-certainty evidence). Compared with as-required FABA alone, any changes in asthma control or spirometry, though favouring as-required FABA/ICS, were small and less than the minimal clinically-important differences. We did not find evidence of differences in asthma-associated quality of life or mortality. For other secondary outcomes FABA/ICS as required was associated with reductions in fractional exhaled nitric oxide, probably reduces the odds of an adverse event (OR 0.82, 95% CI 0.71 to 0.95, 2 RCTs, 3002 participants, moderate-certainty evidence) and may reduce total systemic steroid dose (MD -9.90, 95% CI -19.38 to -0.42, 1 RCT, 443 participants, low-certainty evidence), and with an increase in the daily inhaled steroid dose (MD 77 μg beclomethasone equiv./day, 95% CI 69 to 84, 2 RCTs, 2554 participants, moderate-certainty evidence). FABA/ICS as required versus regular ICS plus FABA as required There may be little or no difference in the number of people with asthma exacerbations requiring systemic steroid with FABA/ICS as required compared with regular ICS (OR 0.79, 95% CI 0.59 to 1.07, 4 RCTs, 8065 participants, low-certainty evidence), equivalent to 81 people out of 1000 in the regular ICS plus FABA group experiencing an exacerbation requiring systemic steroids, compared to 65 (95% CI 49 to 86) out of 1000 FABA/ICS as required group. The odds of an asthma-related hospital admission or emergency department or urgent care visit may be reduced in those taking FABA/ICS as required (OR 0.63, 95% CI 0.44 to 0.91, 4 RCTs, 8065 participants, low-certainty evidence). Compared with regular ICS, any changes in asthma control, spirometry, peak flow rates (PFR), or asthma-associated quality of life, though favouring regular ICS, were small and less than the minimal clinically important differences (MCID). Adverse events, serious adverse events, total systemic corticosteroid dose and mortality were similar between groups, although deaths were rare, so confidence intervals for this analysis were wide. We found moderate-certainty evidence from four trials involving 7180 participants that FABA/ICS as required was likely associated with less average daily exposure to inhaled corticosteroids than those on regular ICS (MD -154.51 μg/day, 95% CI -207.94 to -101.09).
AUTHORS' CONCLUSIONS
We found FABA/ICS as required is clinically effective in adults and adolescents with mild asthma. Their use instead of FABA as required alone reduced exacerbations, hospital admissions or unscheduled healthcare visits and exposure to systemic corticosteroids and probably reduces adverse events. FABA/ICS as required is as effective as regular ICS and reduced asthma-related hospital admissions or unscheduled healthcare visits, and average exposure to ICS, and is unlikely to be associated with an increase in adverse events. Further research is needed to explore use of FABA/ICS as required in children under 12 years of age, use of other FABA/ICS preparations, and long-term outcomes beyond 52 weeks.
Topics: Adolescent; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Anti-Asthmatic Agents; Asthma; Beclomethasone; Budesonide; Child; Disease Progression; Drug Combinations; Formoterol Fumarate; Hospitalization; Humans; Nebulizers and Vaporizers; Prednisolone; Quality of Life; Randomized Controlled Trials as Topic; Terbutaline
PubMed: 33945639
DOI: 10.1002/14651858.CD013518.pub2