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The Cochrane Database of Systematic... Mar 2019Chronic obstructive pulmonary disease (COPD) is a respiratory condition causing accumulation of mucus in the airways, cough, and breathlessness; the disease is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a respiratory condition causing accumulation of mucus in the airways, cough, and breathlessness; the disease is progressive and is the fourth most common cause of death worldwide. Current treatment strategies for COPD are multi-modal and aim to reduce morbidity and mortality and increase patients' quality of life by slowing disease progression and preventing exacerbations. Fixed-dose combinations (FDCs) of a long-acting beta-agonist (LABA) plus a long-acting muscarinic antagonist (LAMA) delivered via a single inhaler are approved by regulatory authorities in the USA, Europe, and Japan for the treatment of COPD. Several LABA/LAMA FDCs are available and recent meta-analyses have clarified their utility versus their mono-components in COPD. Evaluation of the efficacy and safety of once-daily LABA/LAMA FDCs versus placebo will facilitate the comparison of different FDCs in future network meta-analyses.
OBJECTIVES
We assessed the evidence for once-daily LABA/LAMA combinations (delivered in a single inhaler) versus placebo on clinically meaningful outcomes in patients with stable COPD.
SEARCH METHODS
We identified trials from Cochrane Airways' Specialised Register (CASR) and also conducted a search of the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch). We searched CASR and trial registries from their inception to 3 December 2018; we imposed no restriction on language of publication.
SELECTION CRITERIA
We included parallel-group and cross-over randomised controlled trials (RCTs) comparing once-daily LABA/LAMA FDC versus placebo. We included studies reported as full-text, those published as abstract only, and unpublished data. We excluded very short-term trials with a duration of less than 3 weeks. We included adults (≥ 40 years old) with a diagnosis of stable COPD. We included studies that allowed participants to continue using their ICS during the trial as long as the ICS was not part of the randomised treatment.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the search results to determine included studies, extracted data on prespecified outcomes of interest, and assessed the risk of bias of included studies; we resolved disagreements by discussion with a third review author. Where possible, we used a random-effects model to meta-analyse extracted data. We rated all outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system and presented results in 'Summary of findings' tables.
MAIN RESULTS
We identified and included 22 RCTs randomly assigning 8641 people with COPD to either once-daily LABA/LAMA FDC (6252 participants) or placebo (3819 participants); nine studies had a cross-over design. Studies had a duration of between three and 52 weeks (median 12 weeks). The mean age of participants across the included studies ranged from 59 to 65 years and in 21 of 22 studies, participants had GOLD stage II or III COPD. Concomitant inhaled corticosteroid (ICS) use was permitted in all of the included studies (where stated); across the included studies, between 28% to 58% of participants were using ICS at baseline. Six studies evaluated the once-daily combination of IND/GLY (110/50 μg), seven studies evaluated TIO/OLO (2.5/5 or 5/5 μg), eight studies evaluated UMEC/VI (62.5/5, 125/25 or 500/25 μg) and one study evaluated ACD/FOR (200/6, 200/12 or 200/18 μg); all LABA/LAMA combinations were compared with placebo.The risk of bias was generally considered to be low or unknown (insufficient detail provided), with only one study per domain considered to have a high risk of bias except for the domain 'other bias' which was determined to be at high risk of bias in four studies (in three studies, disease severity was greater at baseline in participants receiving LABA/LAMA compared with participants receiving placebo, which would be expected to shift the treatment effect in favour of placebo).Compared to the placebo, the pooled results for the primary outcomes for the once-daily LABA/LAMA arm were as follows: all-cause mortality, OR 1.88 (95% CI 0.81 to 4.36, low-certainty evidence); all-cause serious adverse events (SAEs), OR 1.06 (95% CI 0.88 to 1.28, high-certainty evidence); acute exacerbations of COPD (AECOPD), OR 0.53 (95% CI 0.36 to 0.78, moderate-certainty evidence); adjusted St George's Respiratory Questionnaire (SGRQ) score, MD -4.08 (95% CI -4.80 to -3.36, high-certainty evidence); proportion of SGRQ responders, OR 1.75 (95% CI 1.54 to 1.99). Compared with placebo, the pooled results for the secondary outcomes for the once-daily LABA/LAMA arm were as follows: adjusted trough forced expiratory volume in one second (FEV1), MD 0.20 L (95% CI 0.19 to 0.21, moderate-certainty evidence); adjusted peak FEV1, MD 0.31 L (95% CI 0.29 to 0.32, moderate-certainty evidence); and all-cause AEs, OR 0.95 (95% CI 0.86 to 1.04; high-certainty evidence). No studies reported data for the 6-minute walk test. The results were generally consistent across subgroups for different LABA/LAMA combinations and doses.
AUTHORS' CONCLUSIONS
Compared with placebo, once-daily LABA/LAMA (either IND/GLY, UMEC/VI or TIO/OLO) via a combination inhaler is associated with a clinically significant improvement in lung function and health-related quality of life in patients with mild-to-moderate COPD; UMEC/VI appears to reduce the rate of exacerbations in this population. These conclusions are supported by moderate or high certainty evidence based on studies with an observation period of up to one year.
Topics: Adrenergic beta-2 Receptor Agonists; Aged; Cause of Death; Cross-Over Studies; Disease Progression; Drug Administration Schedule; Drug Combinations; Humans; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Placebos; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 30839102
DOI: 10.1002/14651858.CD012930.pub2 -
Urology May 2019To compare the efficacy and safety of mirabegron and onabotulinumtoxinA in the management of treatment-experienced patients with overactive bladder. (Comparative Study)
Comparative Study Meta-Analysis
The Relative Efficacy and Safety of Mirabegron and OnabotulinumtoxinA in Patients With Overactive Bladder who Have Previously Been Managed With an Antimuscarinic: A Network Meta-analysis.
OBJECTIVE
To compare the efficacy and safety of mirabegron and onabotulinumtoxinA in the management of treatment-experienced patients with overactive bladder.
METHODS
The network meta-analysis was based on evidence from a systematic literature review of randomized controlled trials and a post-hoc analysis of treatment-experienced subpopulations from mirabegron studies.
RESULTS
Nineteen trials described in 21 publications were included.
CONCLUSION
Overall, compared to mirabegron, there was some evidence that onabotulinumtoxinA was associated with improved outcomes, including reductions in the number of micturitions in a 24-hour period, and the number of incontinence episodes. However, mirabegron was associated with a lower risk of urinary tract infections compared with onabotulinumtoxinA.
Topics: Acetanilides; Administration, Oral; Adrenergic beta-3 Receptor Antagonists; Aged; Aged, 80 and over; Bayes Theorem; Botulinum Toxins, Type A; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Muscarinic Antagonists; Network Meta-Analysis; Prognosis; Randomized Controlled Trials as Topic; Retreatment; Thiazoles; Treatment Failure; Treatment Outcome; Urinary Bladder, Overactive; Urodynamics
PubMed: 30790650
DOI: 10.1016/j.urology.2019.02.005 -
Advances in Therapy Mar 2019Maintenance bronchodilator therapy with long-acting β-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) is the cornerstone treatment for patients with...
Maintenance bronchodilator therapy with long-acting β-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) is the cornerstone treatment for patients with stable chronic obstructive pulmonary disease (COPD). Fixed-dose combinations (FDCs) of LABA/LAMA are recommended for the majority of symptomatic COPD patients by global guidelines; regional guidelines such as the Japanese and Korean guidelines also provide similar recommendations for the use of LABA/LAMA FDCs. This review comprehensively describes the latest clinical evidence from key studies on the efficacy and safety of four approved LABA/LAMA fixed-dose combinations: indacaterol/glycopyrronium, vilanterol/umeclidinium, formoterol/aclidinium, and olodaterol/tiotropium. Additionally, in this review we describe the rationale behind the use of LABA/LAMA FDC therapy, key findings from the preclinical and clinical trial evaluation of respective LABA and LAMA monocomponents, and the efficacy and safety of LABA/LAMA FDCs. Special emphasis is placed on the clinical evidence for the monocomponents and LABA/LAMA FDCs from the Asian population. This detailed overview of the efficacy and safety of LABA/LAMA FDCs in global and Asian COPD patients is envisaged to provide a better understanding of the benefits of these therapies and to inform healthcare providers and patients on their appropriate use.Funding: Novartis Pharma K.K.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Asian People; Benzoxazines; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Formoterol Fumarate; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Tiotropium Bromide; Treatment Outcome; Tropanes
PubMed: 30742242
DOI: 10.1007/s12325-019-0893-3 -
Advances in Therapy Mar 2019The objective was to identify the most commonly used patient-reported outcome (PRO) instruments for overactive bladder (OAB), determine which are the most useful for...
INTRODUCTION
The objective was to identify the most commonly used patient-reported outcome (PRO) instruments for overactive bladder (OAB), determine which are the most useful for measuring burden in OAB and characterize the findings of recent studies that have employed PRO instruments to assess OAB symptoms and the effects of treatment.
METHODS
A systematic search of OAB literature published between January 2006 and November 2017 using Medline/PubMed and EMBASE databases.
RESULTS
Of 3425 abstracts and 500 full-text articles reviewed, 58 studies (both clinical trials and observational studies) were included in the review. The most commonly used PRO instruments were the OAB Questionnaire (OAB-q; 64%), followed by the King's Health Questionnaire (KHQ; 31%) and the Patient Perception of Bladder Condition (PCBC; 21%). Synthesis of data from studies using the OAB-q showed that OAB treatment with antimuscarinics, mirabegron and onabotulinumtoxinA all improve health-related quality of life (HRQoL) and symptoms beyond the benefits observed with placebo. The OAB-q could detect dose-response relationships in some studies and demonstrated there were no significant differences across therapies from different drug classes.
CONCLUSION
The HRQoL burden of OAB and response to treatment can be reliably measured by PRO instruments, and the OAB-q is the most commonly used instrument in OAB, particularly in clinical trials of OAB interventions. These data will be useful to provide benchmarks of burden levels for PRO scores obtained among those on contemporary therapies for comparison with outcomes from patients managed with emerging treatments.
FUNDING
Astellas Pharma Global Development, Inc.
Topics: Acetanilides; Botulinum Toxins, Type A; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Patient Reported Outcome Measures; Quality of Life; Surveys and Questionnaires; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive; Urological Agents
PubMed: 30715686
DOI: 10.1007/s12325-019-0880-8 -
The Cochrane Database of Systematic... Dec 2018Several dual bronchodilator combinations of long-acting beta-agonist (LABA) and long-acting muscarinic antagonist (LAMA) have been approved for treatment of stable... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Several dual bronchodilator combinations of long-acting beta-agonist (LABA) and long-acting muscarinic antagonist (LAMA) have been approved for treatment of stable chronic obstructive pulmonary disease (COPD). The current GOLD (Global Initiative for Chronic Obstructive Lung Disease) recommendations suggest the use of LABA/LAMA combinations in people with group B COPD with persistent symptoms, group C COPD with further exacerbations on LAMA therapy alone and group D COPD with or without inhaled corticosteroids (ICS). Fixed-dose combination (FDC) of aclidinium/formoterol is one of the approved LABA/LAMA therapies for people with stable COPD.
OBJECTIVES
To assess the efficacy and safety of combined aclidinium bromide and long-acting beta-agonists in stable COPD.
SEARCH METHODS
We searched the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov, World Health Organization (WHO) trials portal, United States Food and Drug Administration (FDA) and manufacturers' websites as well as the reference list of published trials up to 12 October 2018.
SELECTION CRITERIA
Parallel-group randomised controlled trials (RCTs) assessing combined aclidinium bromide and LABAs in people with stable COPD.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane for data collection and analysis. The primary outcomes were exacerbations requiring a short course of an oral steroid or antibiotic, or both; quality of life measured by a validated scale and non-fatal serious adverse events (SAEs). Where the outcome or study details were not reported, we contacted the study investigators or pharmaceutical company trial co-ordinators (or both) for missing data.
MAIN RESULTS
We identified RCTs comparing aclidinium/formoterol FDC versus aclidinium, formoterol or placebo only. We included seven multicentre trials of four to 52 weeks' duration conducted in outpatient settings. There were 5921 participants, whose mean age ranged from 60.7 to 64.7 years, mostly men with a mean smoking pack-years of 46.4 to 61.3 of which 43.9% to 63.4% were current smokers. They had a moderate-to-severe degree of COPD with a mean postbronchodilator forced expiratory volume in one second (FEV) between 50.5% and 61% of predicted normal and the baseline mean FEV of 1.23 L to 1.43 L. We assessed performance and detection biases as low for all studies whereas selection, attrition and reporting biases were either low or unclear.FDC versus aclidiniumThere was no evidence of a difference between FDC and aclidinium for exacerbations requiring steroids or antibiotics, or both (OR 0.95, 95% CI 0.71 to 1.27; 2 trials, 2156 participants; moderate-certainty evidence); quality of life measured by St George's Respiratory Questionnaire (SGRQ) total score (MD -0.92, 95% CI -2.15 to 0.30); participants with significant improvement in SGRQ score (OR 1.17, 95% CI 0.97 to 1.41; 2 trials, 2002 participants; moderate-certainty evidence); non-fatal SAE (OR 1.19, 95% CI 0.79 to 1.80; 3 trials, 2473 participants; moderate-certainty evidence); hospital admissions due to severe exacerbations (OR 0.62, 95% CI 0.29 to 1.29; 2 trials, 2156 participants; moderate-certainty evidence) or adverse events (OR 0.95, 95% CI 0.76 to 1.18; 3 trials, 2473 participants; moderate-certainty evidence). Compared with aclidinium, FDC improved symptoms (Transitional Dyspnoea Index (TDI) focal score: MD 0.37, 95% CI 0.07 to 0.68; 2 trials, 2013 participants) with a higher chance of achieving a minimal clinically important difference (MCID) of at least one unit improvement (OR 1.34, 95% CI 1.11 to 1.62; high-certainty evidence); the number needed to treat for an additional beneficial outcome (NNTB) being 14 (95% CI 9 to 39).FDC versus formoterolWhen compared to formoterol, combination therapy reduced exacerbations requiring steroids or antibiotics, or both (OR 0.78, 95% CI 0.62 to 0.99; 3 trials, 2694 participants; high-certainty evidence); may decrease SGRQ total score (MD -1.88, 95% CI -3.10 to -0.65; 2 trials, 2002 participants; low-certainty evidence; MCID for SGRQ is 4 units); increased TDI focal score (MD 0.42, 95% CI 0.11 to 0.72; 2 trials, 2010 participants) with more participants attaining an MCID (OR 1.30, 95% CI 1.07 to 1.56; high-certainty evidence) and an NNTB of 16 (95% CI 10 to 60). FDC lowered the risk of adverse events compared to formoterol (OR 0.78, 95% CI 0.65 to 0.93; 5 trials, 3140 participants; high-certainty evidence; NNTB 22). However, there was no difference between FDC and formoterol for hospital admissions, all-cause mortality and non-fatal SAEs.FDC versus placeboCompared with placebo, FDC demonstrated no evidence of a difference in exacerbations requiring steroids or antibiotics, or both (OR 0.82, 95% CI 0.60 to 1.12; 2 trials, 1960 participants; moderate-certainty evidence) or hospital admissions due to severe exacerbations (OR 0.55, 95% CI 0.25 to 1.18; 2 trials, 1960 participants; moderate-certainty evidence), although estimates were uncertain. Quality of life measure by SGRQ total score was significantly better with FDC compared to placebo (MD -2.91, 95% CI -4.33 to -1.50; 2 trials, 1823 participants) resulting in a corresponding increase in SGRQ responders who achieved at least four units decrease in SGRQ total score (OR 1.72, 95% CI 1.39 to 2.13; high-certainty evidence) with an NNTB of 7 (95% CI 5 to 12). FDC also improved symptoms measured by TDI focal score (MD 1.32, 95% CI 0.96 to 1.69; 2 studies, 1832 participants) with more participants attaining at least one unit improvement in TDI focal score (OR 2.51, 95% CI 2.02 to 3.11; high-certainty evidence; NNTB 4). There were no differences in non-fatal SAEs, adverse events and all-cause mortality between FDC and placebo.Combination therapy significantly improved trough FEV compared to aclidinium, formoterol or placebo.
AUTHORS' CONCLUSIONS
FDC improved dyspnoea and lung function compared to aclidinium, formoterol or placebo, and this translated into an increase in the number of responders on combination treatment. Quality of life was better with combination compared to formoterol or placebo. There was no evidence of a difference between FDC and monotherapy or placebo for exacerbations, hospital admissions, mortality, non-fatal SAEs or adverse events. Studies reported a lower risk of moderate exacerbations and adverse events with FDC compared to formoterol; however, larger studies would yield a more precise estimate for these outcomes.
Topics: Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Disease Progression; Drug Therapy, Combination; Dyspnea; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Tropanes
PubMed: 30536566
DOI: 10.1002/14651858.CD011594.pub2 -
The Cochrane Database of Systematic... Dec 2018Long-acting bronchodilators such as long-acting β-agonist (LABA), long-acting muscarinic antagonist (LAMA), and LABA/inhaled corticosteroid (ICS) combinations have been... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Long-acting bronchodilators such as long-acting β-agonist (LABA), long-acting muscarinic antagonist (LAMA), and LABA/inhaled corticosteroid (ICS) combinations have been used in people with moderate to severe chronic obstructive pulmonary disease (COPD) to control symptoms such as dyspnoea and cough, and prevent exacerbations. A number of LABA/LAMA combinations are now available for clinical use in COPD. However, it is not clear which group of above mentioned inhalers is most effective or if any specific formulation works better than the others within the same group or class.
OBJECTIVES
To compare the efficacy and safety of available formulations from four different groups of inhalers (i.e. LABA/LAMA combination, LABA/ICS combination, LAMA and LABA) in people with moderate to severe COPD. The review will update previous systematic reviews on dual combination inhalers and long-acting bronchodilators to answer the questions described above using the strength of a network meta-analysis (NMA).
SEARCH METHODS
We identified studies from the Cochrane Airways Specialised Register, which contains several databases. We also conducted a search of ClinicalTrials.gov and manufacturers' websites. The most recent searches were conducted on 6 April 2018.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that recruited people aged 35 years or older with a diagnosis of COPD and a baseline forced expiratory volume in one second (FEV1) of less than 80% of predicted. We included studies of at least 12 weeks' duration including at least two active comparators from one of the four inhaler groups.
DATA COLLECTION AND ANALYSIS
We conducted NMAs using a Bayesian Markov chain Monte Carlo method. We considered a study as high risk if recruited participants had at least one COPD exacerbation within the 12 months before study entry and as low risk otherwise. Primary outcomes were COPD exacerbations (moderate to severe and severe), and secondary outcomes included symptom and quality-of-life scores, safety outcomes, and lung function. We collected data only for active comparators and did not consider placebo was not considered. We assumed a class/group effect when a fixed-class model fitted well. Otherwise we used a random-class model to assess intraclass/group differences. We supplemented the NMAs with pairwise meta-analyses.
MAIN RESULTS
We included a total of 101,311 participants from 99 studies (26 studies with 32,265 participants in the high-risk population and 73 studies with 69,046 participants in the low-risk population) in our systematic review. The median duration of studies was 52 weeks in the high-risk population and 26 weeks in the low-risk population (range 12 to 156 for both populations). We considered the quality of included studies generally to be good.The NMAs suggested that the LABA/LAMA combination was the highest ranked treatment group to reduce COPD exacerbations followed by LAMA in the both populations.There is evidence that the LABA/LAMA combination decreases moderate to severe exacerbations compared to LABA/ICS combination, LAMA, and LABA in the high-risk population (network hazard ratios (HRs) 0.86 (95% credible interval (CrI) 0.76 to 0.99), 0.87 (95% CrI 0.78 to 0.99), and 0.70 (95% CrI 0.61 to 0.8) respectively), and that LAMA decreases moderate to severe exacerbations compared to LABA in the high- and low-risk populations (network HR 0.80 (95% CrI 0.71 to 0.88) and 0.87 (95% CrI 0.78 to 0.97), respectively). There is evidence that the LABA/LAMA combination reduces severe exacerbations compared to LABA/ICS combination and LABA in the high-risk population (network HR 0.78 (95% CrI 0.64 to 0.93) and 0.64 (95% CrI 0.51 to 0.81), respectively).There was a general trend towards a greater improvement in symptom and quality-of-life scores with the combination therapies compared to monotherapies, and the combination therapies were generally ranked higher than monotherapies.The LABA/ICS combination was the lowest ranked in pneumonia serious adverse events (SAEs) in both populations. There is evidence that the LABA/ICS combination increases the odds of pneumonia compared to LAMA/LABA combination, LAMA and LABA (network ORs: 1.69 (95% CrI 1.20 to 2.44), 1.78 (95% CrI 1.33 to 2.39), and 1.50 (95% CrI 1.17 to 1.92) in the high-risk population and network or pairwise OR: 2.33 (95% CI 1.03 to 5.26), 2.02 (95% CrI 1.16 to 3.72), and 1.93 (95% CrI 1.29 to 3.22) in the low-risk population respectively). There were significant overlaps in the rank statistics in the other safety outcomes including mortality, total, COPD, and cardiac SAEs, and dropouts due to adverse events.None of the differences in lung function met a minimal clinically important difference criterion except for LABA/LAMA combination versus LABA in the high-risk population (network mean difference 0.13 L (95% CrI 0.10 to 0.15). The results of pairwise meta-analyses generally agreed with those of the NMAs. There is no evidence to suggest intraclass/group differences except for lung function at 12 months in the high-risk population.
AUTHORS' CONCLUSIONS
The LABA/LAMA combination was the highest ranked treatment group to reduce COPD exacerbations although there was some uncertainty in the results. LAMA containing inhalers may have an advantage over those without a LAMA for preventing COPD exacerbations based on the rank statistics. Combination therapies appear more effective than monotherapies for improving symptom and quality-of-life scores. ICS-containing inhalers are associated with an increased risk of pneumonia.Our most comprehensive review including intraclass/group comparisons, free combination therapies, 99 studies, and 20 outcomes for each high- and low-risk population summarises the current literature and could help with updating existing COPD guidelines.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Bayes Theorem; Bronchodilator Agents; Disease Progression; Drug Therapy, Combination; Humans; Middle Aged; Monte Carlo Method; Muscarinic Antagonists; Network Meta-Analysis; Pneumonia; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Secondary Prevention
PubMed: 30521694
DOI: 10.1002/14651858.CD012620.pub2 -
BMJ Open Nov 2018To evaluate persistence and adherence of oral pharmacotherapy used in the treatment of overactive bladder (OAB) in a real-world setting.
PURPOSE
To evaluate persistence and adherence of oral pharmacotherapy used in the treatment of overactive bladder (OAB) in a real-world setting.
MATERIALS AND METHODS
Systematic literature searches of six electronic publication databases were performed to identify observational studies of patients with OAB treated with antimuscarinics and/or mirabegron. Studies obtaining persistence and adherence data from sources other than electronic prescription claims were excluded. Reference lists of identified studies and relevant systematic reviews were assessed to identify additional relevant studies.
RESULTS
The search identified 3897 studies, of which 30 were included. Overall, persistence ranged from 5% to 47%. In studies reporting data for antimuscarinics and mirabegron (n=3), 1-year persistence was 12%-25% and 32%-38%, respectively. Median time to discontinuation was <5 months for antimuscarinics (except one study (6.5 months)) and 5.6-7.4 months for mirabegron. The proportion of patients adherent at 1 year varied between 15% and 44%. In studies reporting adherence for antimuscarinics and mirabegron, adherence was higher with mirabegron (mean medication possession ratio (MPR): 0.59 vs 0.41-0.53; mean proportion of days covered: 0.66 vs 0.55; and median MPR: 0.65 vs 0.19-0.49). Reported determinants of persistence and adherence included female (sex), older age group, use of extended-release formulation and treatment experience.
CONCLUSION
Most patients with OAB discontinued oral OAB pharmacotherapy and were non-adherent 1 year after treatment initiation. In general, mirabegron was associated with greater persistence and adherence compared with antimuscarinics. Combined with existing clinical trial evidence, this real-world review merits consideration of mirabegron for first-line pharmacological treatment among patients with OAB.
PROSPERO REGISTRATION NUMBER
CRD42017059894.
Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Humans; Medication Adherence; Muscarinic Antagonists; Thiazoles; Urinary Bladder, Overactive
PubMed: 30467131
DOI: 10.1136/bmjopen-2018-021889 -
BMJ (Clinical Research Ed.) Nov 2018To compare the rate of moderate to severe exacerbations between triple therapy and dual therapy or monotherapy in patients with chronic obstructive pulmonary disease... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To compare the rate of moderate to severe exacerbations between triple therapy and dual therapy or monotherapy in patients with chronic obstructive pulmonary disease (COPD).
DESIGN
Systematic review and meta-analysis of randomised controlled trials.
DATA SOURCES
PubMed, Embase, Cochrane databases, and clinical trial registries searched from inception to April 2018.
ELIGIBILITY CRITERIA
Randomised controlled trials comparing triple therapy with dual therapy or monotherapy in patients with COPD were eligible. Efficacy and safety outcomes of interest were also available.
DATA EXTRACTION AND SYNTHESIS
Data were collected independently. Meta-analyses were conducted to calculate rate ratios, hazard ratios, risk ratios, and mean differences with 95% confidence intervals. Quality of evidence was summarised in accordance with GRADE methodology (grading of recommendations assessment, development, and evaluation).
RESULTS
21 trials (19 publications) were included. Triple therapy consisted of a long acting muscarinic antagonist (LAMA), long acting β agonist (LABA), and inhaled corticosteroid (ICS). Triple therapy was associated with a significantly reduced rate of moderate or severe exacerbations compared with LAMA monotherapy (rate ratio 0.71, 95% confidence interval 0.60 to 0.85), LAMA and LABA (0.78, 0.70 to 0.88), and ICS and LABA (0.77, 0.66 to 0.91). Trough forced expiratory volume in 1 second (FEV1) and quality of life were favourable with triple therapy. The overall safety profile of triple therapy is reassuring, but pneumonia was significantly higher with triple therapy than with dual therapy of LAMA and LABA (relative risk 1.53, 95% confidence interval 1.25 to 1.87).
CONCLUSIONS
Use of triple therapy resulted in a lower rate of moderate or severe exacerbations of COPD, better lung function, and better health related quality of life than dual therapy or monotherapy in patients with advanced COPD.
STUDY REGISTRATION
Prospero CRD42018077033.
Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life
PubMed: 30401700
DOI: 10.1136/bmj.k4388 -
International Journal of Chronic... 2018To assess the comparative efficacy of short-acting muscarinic antagonists (SAMAs), long-acting muscarinic antagonists (LAMAs), LAMA in combination with long-acting... (Meta-Analysis)
Meta-Analysis
PURPOSE
To assess the comparative efficacy of short-acting muscarinic antagonists (SAMAs), long-acting muscarinic antagonists (LAMAs), LAMA in combination with long-acting beta-agonists (LABAs; LAMA/LABAs) and inhaled corticosteroids (ICS) in combination with LABA (ICS/LABAs) for the maintenance treatment of COPD.
MATERIALS AND METHODS
We systematically reviewed 74 randomized controlled trials (74,832 participants) published up to 15 November 2017, which compared any of the interventions (SAMA [ipratropium], LAMA [aclidinium, glycopyrronium, tiotropium, umeclidinium], LAMA/LABA [aclidinium/formoterol, indacaterol/glycopyrronium, tiotropium/olodaterol, umeclidinium/vilanterol] and ICS/LABA [fluticasone/vilanterol, budesonide/formoterol, salmeterol/fluticasone]) with each other or with placebo. A random-effects network meta-analysis combining direct and indirect evidence was conducted to examine the change from baseline in trough FEV, transition dyspnea index, St George's Respiratory Questionnaire and frequency of adverse events at weeks 12 and 24.
RESULTS
Inconsistency models were not statistically significant for all outcomes. LAMAs, LAMA/LABAs and ICS/LABAs led to a significantly greater improvement in trough FEV compared with placebo and SAMA monotherapy at weeks 12 and 24. All LAMA/LABAs, except aclidinium/formoterol, were statistically significantly better than LAMA monotherapy and ICS/LABAs in improving trough FEV. Among the LAMAs, umeclidinium showed statistically significant improvement in trough FEV at week 12 compared to tiotropium and glycopyrronium, but the results were not clinically significant. LAMA/LABAs had the highest probabilities of being ranked the best agents in FEV improvement. Similar trends were observed for the transition dyspnea index and St George's Respiratory Questionnaire outcomes. There were no significant differences in the incidences of adverse events among all treatment options.
CONCLUSION
LAMA/LABA showed the greatest improvement in trough FEV at weeks 12 and 24 compared with the other inhaled drug classes, while SAMA showed the least improvement. There were no significant differences among the LAMAs and LAMA/LABAs within their respective classes.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory System Agents; Treatment Outcome
PubMed: 30349228
DOI: 10.2147/COPD.S173472 -
International Journal of Chronic... 2018The aim of this study was to assess the current evidence for long-acting β-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) in the...
OBJECTIVES
The aim of this study was to assess the current evidence for long-acting β-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) in the treatment of COPD.
MATERIALS AND METHODS
A systematic literature search of randomized controlled trials published in English up to September 2017 of LABA/LAMA FDCs vs LABA or LAMA or LABA/inhaled corticosteroid (ICS) FDCs in COPD patients was performed using PubMed, Embase, Scopus, and Google Scholar. Outcomes including forced expiratory volume in 1 second (FEV), Transition Dyspnea Index (TDI) scores, St George's Respiratory Questionnaire (SGRQ) scores, exacerbations, exercise tolerance (endurance time [ET]), inspiratory capacity (IC), and rescue medication use were evaluated.
RESULTS
In total, 27 studies were included in the review. LABA/LAMA FDCs significantly improved lung function (FEV) at 12 weeks compared with LABA or LAMA or LABA/ICS. These effects were maintained over time. Significant improvements with LABA/LAMA FDCs vs each evaluated comparator were also observed in TDI and SGRQ scores, even if significant differences between different LABA/LAMA FDCs were detected. Only the LABA/LAMA FDC indacaterol/glycopyrronium has shown superiority vs LAMA and LABA/ICS for reducing exacerbation rates, while olodaterol/tiotropium and indacaterol/glycopyrronium have been shown to improve ET and IC vs the active comparators. Rescue medication use was significantly reduced by LABA/LAMA FDCs vs the evaluated comparators. LABA/LAMA FDCs were safe, with no increase in the risk of adverse events with LABA/LAMA FDCs vs the monocomponents.
CONCLUSION
Evidence supporting the efficacy of LABA/LAMA FDCs for COPD is heterogeneous, particularly for TDI and SGRQ scores, exacerbation rates, ET, and IC. So far, indacaterol/glycopyrronium is the LABA/LAMA FDC that has the strongest evidence for superiority vs LABA, LAMA, and LABA/ICS FDCs across the evaluated outcomes. LABA/LAMA FDCs were safe; however, more data should be collected in a real-world setting to confirm their safety.
Topics: Adrenergic beta-2 Receptor Agonists; Delayed-Action Preparations; Drug Combinations; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Respiratory Function Tests; Treatment Outcome
PubMed: 30323582
DOI: 10.2147/COPD.S170606