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The Cochrane Database of Systematic... Jan 2015Indacaterol is an inhaled long-acting beta2-agonist that is administered once daily and has been investigated as a treatment for chronic obstructive pulmonary disease... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Indacaterol is an inhaled long-acting beta2-agonist that is administered once daily and has been investigated as a treatment for chronic obstructive pulmonary disease (COPD). Four different doses have been investigated (75 mcg, 150 mcg, 300 mcg and 600 mcg). The relative effects of different doses of once-daily indacaterol in the management of patients with COPD are uncertain.
OBJECTIVES
To compare the efficacy and safety of indacaterol versus placebo and alternative twice-daily long-acting beta2-agonists for the treatment of patients with stable COPD.
SEARCH METHODS
We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), handsearched respiratory journals and meeting abstracts and searched the Novartis trials registry and ClinicalTrials.gov. The date of the most recent search was 8 November 2014.
SELECTION CRITERIA
We included all randomised controlled trials comparing indacaterol at any dose versus placebo or alternative long-acting beta2-agonists. Trials were required to be of at least 12 weeks' duration and had to include adults older than 18 years with a confirmed spirometric diagnosis of COPD.
DATA COLLECTION AND ANALYSIS
Two review authors (JBG, EJD) independently assessed for possible inclusion all citations identified as a result of the search. Disagreements were resolved through discussion or, if required, through resolution by a third review author (RWB). One review author (JBG) extracted data from trials identified by the search and entered these data into Review Manager 5.1 for statistical analysis. Data entry was cross-checked by a second review author (EJD, CJC).
MAIN RESULTS
A total of 13 trials with 9961 participants were included in the review. Ten trials with a total of 8562 participants involved an indacaterol versus placebo comparison. Five trials with a total of 4133 participants involved an indacaterol versus twice-daily beta2-agonist comparison. The comparator beta2-agonists were salmeterol, formoterol and eformoterol. One of these trials, with a total of 90 participants, provided no data that could be used in this review. Two trials included both indacaterol versus placebo and indacaterol versus twice-daily beta2-agonist comparisons. Trials were between 12 weeks and 52 weeks in duration. Overall the quality of the evidence was strong, and risk of significant bias was minimal in most of the included studies. Enrolled participants had stable COPD across a range of spirometric severities. Forced expiratory volume in 1 second (FEV1) was generally between 30% and 80% predicted, and a mean FEV1 of approximately 50% was predicted in most studies. Patients with concurrent respiratory disease, including asthma, were excluded. Concomitant use of inhaled corticosteroids was permitted.The primary objectives were to compare trough FEV1 at the end of dosing, exacerbation rates and quality of life. Significant adverse events, mortality and dyspnoea were included as secondary outcomes. Compared with placebo, a significant and clinically relevant improvement in trough FEV1 was noted with indacaterol (mean difference (MD) 149.11, 95% confidence interval (CI) 137.09 to 161.12). In addition, compared with placebo, a significant improvement in mean St George Respiratory Questionaire (SGRQ) score (MD -3.60, 95% CI -4.36 to -2.83) was reported, and the proportion of participants experiencing clinically relevant improvement in SGRQ score was significantly greater (odds ratio (OR) 1.63, 95% CI 1.46 to 1.84). Compared with twice-daily beta2-agonists, a small but statistically significant increase in trough FEV1 was seen with indacaterol (MD 61.71 mL, 95% CI 41.24 to 82.17). Differences between indacaterol and twice-daily beta2-agonists in mean SGRQ scores (MD -0.81, 95% CI -2.28 to 0.66) and in the proportions of participants achieving clinically relevant improvements in SGRQ scores (OR 1.07, 95% CI 0.87 to 1.32) were not statistically significant, but the confidence intervals are too wide to permit the conclusion that the treatments were equivalent. Data were insufficient for analysis of differences in exacerbation rates for both placebo and twice-daily beta2-agonist comparisons.
AUTHORS' CONCLUSIONS
For patients with stable COPD, use of indacaterol versus placebo results in statistically significant and clinically meaningful improvements in lung function and quality of life. The clinical benefit for lung function is at least as good as that seen with twice-daily long-acting beta2-agonists. The comparative effect on quality of life remains uncertain, as important differences cannot be excluded.
Topics: Adrenergic beta-2 Receptor Agonists; Drug Administration Schedule; Forced Expiratory Volume; Formoterol Fumarate; Humans; Indans; Pulmonary Disease, Chronic Obstructive; Quinolones; Randomized Controlled Trials as Topic; Salmeterol Xinafoate
PubMed: 25575340
DOI: 10.1002/14651858.CD010139.pub2 -
The Cochrane Database of Systematic... Sep 2014Around 16 million cases of whooping cough (pertussis) occur worldwide each year, mostly in low-income countries. Much of the morbidity of whooping cough in children and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Around 16 million cases of whooping cough (pertussis) occur worldwide each year, mostly in low-income countries. Much of the morbidity of whooping cough in children and adults is due to the effects of the paroxysmal cough. Cough treatments proposed include corticosteroids, beta2-adrenergic agonists, pertussis-specific immunoglobulin, antihistamines and possibly leukotriene receptor antagonists (LTRAs).
OBJECTIVES
To assess the effectiveness and safety of interventions to reduce the severity of paroxysmal cough in whooping cough in children and adults.
SEARCH METHODS
We updated our searches of the Cochrane Central Register of Controlled Trials (CENTRAL, 2014, Issue 1), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, the Database of Abstracts of Reviews of Effects (DARE 2014, Issue 2), accessed from The Cochrane Library, MEDLINE (1950 to 30 January 2014), EMBASE (1980 to 30 January 2014), AMED (1985 to 30 January 2014), CINAHL (1980 to 30 January 2014) and LILACS (30 January 2014). We searched Current Controlled Trials to identify trials in progress.
SELECTION CRITERIA
We selected randomised controlled trials (RCTs) and quasi-RCTs of any intervention (excluding antibiotics and vaccines) to suppress the cough in whooping cough.
DATA COLLECTION AND ANALYSIS
Two review authors (SB, MT) independently selected trials, extracted data and assessed the quality of each trial for this review in 2009. Two review authors (SB, KW) independently reviewed additional studies identified by the updated searches in 2012 and 2014. The primary outcome was frequency of paroxysms of coughing. Secondary outcomes were frequency of vomiting, frequency of whoop, frequency of cyanosis (turning blue), development of serious complications, mortality from any cause, side effects due to medication, admission to hospital and duration of hospital stay.
MAIN RESULTS
We included 12 trials of varying sample sizes (N = 9 to 135), mainly from high-income countries, including a total of 578 participants. Ten trials recruited children (N = 448 participants). Two trials recruited adolescents and adults (N = 130 participants). We considered only three trials to be of high methodological quality (one trial each of diphenhydramine, pertussis immunoglobulin and montelukast). Included studies did not show a statistically significant benefit for any of the interventions. Only six trials, including a total of 196 participants, reported data in sufficient detail for analysis. Diphenhydramine did not change coughing episodes; the mean difference (MD) of coughing spells per 24 hours was 1.9; 95% confidence interval (CI) -4.7 to 8.5 (N = 49 participants from one trial). One trial on pertussis immunoglobulin reported a possible mean reduction of -3.1 whoops per 24 hours (95% CI -6.2 to 0.02, N = 47 participants) but no change in hospital stay (MD -0.7 days; 95% CI -3.8 to 2.4, N = 46 participants). Dexamethasone did not show a clear decrease in length of hospital stay (MD -3.5 days; 95% CI -15.3 to 8.4, N = 11 participants from one trial) and salbutamol showed no change in coughing paroxysms per day (MD -0.2; 95% CI -4.1 to 3.7, N = 42 participants from two trials). Only one trial comparing pertussis immunoglobulin versus placebo (N = 47 participants) reported data on adverse events: 4.3% in the treatment group (rash) versus 5.3% in the placebo group (loose stools, pain and swelling at injection site).
AUTHORS' CONCLUSIONS
There is insufficient evidence to draw conclusions about the effectiveness of interventions for the cough in whooping cough. More high-quality trials are needed to assess the effectiveness of potential antitussive treatments in patients with whooping cough.
Topics: Acetates; Adolescent; Adult; Albuterol; Anti-Inflammatory Agents; Bordetella pertussis; Child; Cough; Cyclopropanes; Dexamethasone; Diphenhydramine; Histamine H1 Antagonists; Humans; Immunoglobulins; Length of Stay; Quinolines; Randomized Controlled Trials as Topic; Sulfides; Whooping Cough
PubMed: 25243777
DOI: 10.1002/14651858.CD003257.pub5 -
Minerva Anestesiologica May 2015Our objective was to systematically review the effect of pharmacological therapies on mortality in patients with acute respiratory distress syndrome (ARDS), focusing on... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Our objective was to systematically review the effect of pharmacological therapies on mortality in patients with acute respiratory distress syndrome (ARDS), focusing on randomized controlled trials (RCTs) published since a previous review in 2004.
METHODS
We updated previous searches and searched OVID versions of MEDLINE, EMBASE and CENTRAL (to January 2013) and proceedings from conferences and bibliographies of included studies. We included RCTs of pharmacologic therapies compared with placebo or no therapy for adult patients with ARDS, using authors' definitions, which reported on mortality (≤ 3 months after randomization). We excluded subgroups of patients with ARDS reported in RCTs enrolling other populations and RCTs of therapies to prevent ARDS, nutritional or fluid interventions, inhaled nitric oxide, therapies coupled to a mechanical ventilation strategy, or oxygen. Two reviewers independently screened citations, selected articles for inclusion, and abstracted clinical and methodological data from included studies with disagreements resolved by a third reviewer. Mortality data were pooled using random-effects models.
RESULTS
From 13461 citations, 58 trials (6635 patients) of 21 classes of medications met selection criteria; 26 trials (3880 patients) were published after 2003. Meta-analyses showed reduced 28-day mortality with a 48-hour infusion of cis-atracurium in early ARDS (relative risk 0.66, 95% confidence interval 0.50 to 0.87; 431 patients, 138 deaths). There was no effect on mortality with granulocyte-macrophage colony stimulating factor, late low-dose methylprednisolone, neutrophil elastase inhibitors, intravenous salbutamol, surfactant, or N-acetylcysteine; each meta-analysis included ≥ 1 trial published after 2003. Seven single trials of other treatments published after 2003 showed no effect. Meta-analysis of older trials of prostaglandin E1 also showed no effect.
CONCLUSION
Effective pharmacotherapy for ARDS remains extremely limited. Cis-atracurium is a promising treatment for early moderate-severe ARDS (using Berlin definition nomenclature) and merits further investigation in a large RCT.
Topics: Atracurium; Humans; Neuromuscular Nondepolarizing Agents; Respiratory Distress Syndrome
PubMed: 24937499
DOI: No ID Found -
The Cochrane Database of Systematic... Jun 2014Bronchiolitis is an acute, viral lower respiratory tract infection affecting infants and is sometimes treated with bronchodilators. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Bronchiolitis is an acute, viral lower respiratory tract infection affecting infants and is sometimes treated with bronchodilators.
OBJECTIVES
To assess the effects of bronchodilators on clinical outcomes in infants (0 to 12 months) with acute bronchiolitis.
SEARCH METHODS
We searched CENTRAL 2013, Issue 12, MEDLINE (1966 to January Week 2, 2014) and EMBASE (1998 to January 2014).
SELECTION CRITERIA
Randomized controlled trials (RCTs) comparing bronchodilators (other than epinephrine) with placebo for bronchiolitis.
DATA COLLECTION AND ANALYSIS
Two authors assessed trial quality and extracted data. We obtained unpublished data from trial authors.
MAIN RESULTS
We included 30 trials (35 data sets) representing 1992 infants with bronchiolitis. In 11 inpatient and 10 outpatient studies, oxygen saturation did not improve with bronchodilators (mean difference (MD) -0.43, 95% confidence interval (CI) -0.92 to 0.06, n = 1242). Outpatient bronchodilator treatment did not reduce the rate of hospitalization (11.9% in bronchodilator group versus 15.9% in placebo group, odds ratio (OR) 0.75, 95% CI 0.46 to 1.21, n = 710). Inpatient bronchodilator treatment did not reduce the duration of hospitalization (MD 0.06, 95% CI -0.27 to 0.39, n = 349).Effect estimates for inpatients (MD -0.62, 95% CI -1.40 to 0.16) were slightly larger than for outpatients (MD -0.25, 95% CI -0.61 to 0.11) for oximetry. Oximetry outcomes showed significant heterogeneity (I(2) statistic = 81%). Including only studies with low risk of bias had little impact on the overall effect size of oximetry (MD -0.38, 95% CI -0.75 to 0.00) but results were close to statistical significance.In eight inpatient studies, there was no change in average clinical score (standardized MD (SMD) -0.14, 95% CI -0.41 to 0.12) with bronchodilators. In nine outpatient studies, the average clinical score decreased slightly with bronchodilators (SMD -0.42, 95% CI -0.79 to -0.06), a statistically significant finding of questionable clinical importance. The clinical score outcome showed significant heterogeneity (I(2) statistic = 73%). Including only studies with low risk of bias reduced the heterogeneity but had little impact on the overall effect size of average clinical score (SMD -0.22, 95% CI -0.41 to -0.03).Sub-analyses limited to nebulized albuterol or salbutamol among outpatients (nine studies) showed no effect on oxygen saturation (MD -0.19, 95% CI -0.59 to 0.21, n = 572), average clinical score (SMD -0.36, 95% CI -0.83 to 0.11, n = 532) or hospital admission after treatment (OR 0.77, 95% CI 0.44 to 1.33, n = 404).Adverse effects included tachycardia, oxygen desaturation and tremors.
AUTHORS' CONCLUSIONS
Bronchodilators such as albuterol or salbutamol do not improve oxygen saturation, do not reduce hospital admission after outpatient treatment, do not shorten the duration of hospitalization and do not reduce the time to resolution of illness at home. Given the adverse side effects and the expense associated with these treatments, bronchodilators are not effective in the routine management of bronchiolitis. This meta-analysis continues to be limited by the small sample sizes and the lack of standardized study design and validated outcomes across the studies. Future trials with large sample sizes, standardized methodology across clinical sites and consistent assessment methods are needed to answer completely the question of efficacy.
Topics: Acute Disease; Albuterol; Ambulatory Care; Bronchiolitis; Bronchodilator Agents; Hospitalization; Humans; Infant; Infant, Newborn; Oxygen; Randomized Controlled Trials as Topic
PubMed: 24937099
DOI: 10.1002/14651858.CD001266.pub4 -
The Cochrane Database of Systematic... Jun 2014Preterm birth, defined as birth between 20 and 36 completed weeks, is a major contributor to perinatal morbidity and mortality globally. Oxytocin receptor antagonists... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Preterm birth, defined as birth between 20 and 36 completed weeks, is a major contributor to perinatal morbidity and mortality globally. Oxytocin receptor antagonists (ORA), such as atosiban, have been specially developed for the treatment of preterm labour. ORA have been proposed as effective tocolytic agents for women in preterm labour to prolong pregnancy with fewer side effects than other tocolytic agents.
OBJECTIVES
To assess the effects on maternal, fetal and neonatal outcomes of tocolysis with ORA for women with preterm labour compared with placebo or any other tocolytic agent.
SEARCH METHODS
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 December 2013).
SELECTION CRITERIA
We included all randomised controlled trials (published and unpublished) of ORA for tocolysis of labour between 20 and 36 completed weeks' gestation.
DATA COLLECTION AND ANALYSIS
Two review authors independently evaluated methodological quality and extracted trial data. When required, we sought additional data from trial authors. Results are presented as risk ratio (RR) for categorical and mean difference (MD) for continuous data with the 95% confidence intervals (CI). Where appropriate, the number needed to treat for benefit (NNTB) and the number needed to treat for harm (NNTH) were calculated.
MAIN RESULTS
This review update includes eight additional studies (790 women), giving a total of 14 studies involving 2485 women.Four studies (854 women) compared ORA (three used atosiban and one barusiban) with placebo. Three studies were considered at low risk of bias in general (blinded allocation to treatment and intervention), the fourth study did not adequately blind the intervention. No difference was shown in birth less than 48 hours after trial entry (average RR 1.05, 95% CI 0.15 to 7.43; random-effects, (two studies, 152 women), perinatal mortality (RR 2.25, 95% CI 0.79 to 6.38; two studies, 729 infants), or major neonatal morbidity. ORA (atosiban) resulted in a small reduction in birthweight (MD -138.86 g, 95% CI -250.53 to -27.18; two studies with 676 infants). In one study, atosiban resulted in an increase in extremely preterm birth (before 28 weeks' gestation) (RR 3.11, 95% CI 1.02 to 9.51; NNTH 31, 95% CI 8 to 3188) and infant deaths (up to 12 months) (RR 6.13, 95% CI 1.38 to 27.13; NNTH 28, 95% CI 6 to 377). However, this finding may be confounded due to randomisation of more women with pregnancy less than 26 weeks' gestation to atosiban. ORA also resulted in an increase in maternal adverse drug reactions requiring cessation of treatment in comparison with placebo (RR 4.02, 95% CI 2.05 to 7.85; NNTH 12, 95% CI 5 to 33). No differences were shown in preterm birth less than 37 weeks' gestation or any other adverse neonatal outcomes. No differences were evident by type of ORA, although data were limited.Eight studies (1402 women) compared ORA (atosiban only) with betamimetics; four were considered of low risk of bias (blinded allocation to treatment and to intervention). No statistically significant difference was shown in birth less than 48 hours after trial entry (RR 0.89, 95% CI 0.66 to 1.22; eight studies with 1389 women), very preterm birth (RR 1.70, 95% CI 0.89 to 3.23; one study with 145 women), extremely preterm birth (RR 0.84, 95% CI 0.37 to 1.92; one study with 244 women) or perinatal mortality (RR 0.55, 95% CI 0.21 to 1.48; three studies with 816 infants). One study (80 women), of unclear methodological quality, showed an increase in the interval between trial entry and birth (MD 22.90 days, 95% CI 18.03 to 27.77). No difference was shown in any reported measures of major neonatal morbidity (although numbers were small). ORA (atosiban) resulted in less maternal adverse effects requiring cessation of treatment (RR 0.05, 95% CI 0.02 to 0.11; NNTB 6, 95% CI 6 to 6; five studies with 1161 women).Two studies including (225 women) compared ORA (atosiban) with calcium channel blockers (CCB) (nifedipine only). The studies were considered as having high risk of bias as neither study blinded the intervention and in one study it was not known if allocation was blinded. No difference was shown in birth less than 48 hours after trial entry (average RR 1.09, 95% CI 0.44 to 2.73, random-effects; two studies, 225 women) and extremely preterm birth (RR 2.14, 95% CI 0.20 to 23.11; one study, 145 women). No data were available for the outcome of perinatal mortality. One small trial (145 women), which did not employ blinding of the intervention, showed an increase in the number of preterm births (before 37 weeks' gestation) (RR 1.56, 95% CI 1.13 to 2.14; NNTH 5, 95% CI 3 to 19), a lower gestational age at birth (MD -1.20 weeks, 95% CI -2.15 to -0.25) and an increase in admission to neonatal intensive care unit (RR 1.70, 95% CI 1.17 to 2.47; NNTH 5, 95% CI 3 to 20). ORA (atosiban) resulted in less maternal adverse effects (RR 0.38, 95% CI 0.21 to 0.68; NNTB 6, 95% CI 5 to 12; two studies, 225 women) but not maternal adverse effects requiring cessation of treatment (RR 0.36, 95% CI 0.01 to 8.62; one study, 145 women). No longer-term outcome data were included.
AUTHORS' CONCLUSIONS
This review did not demonstrate superiority of ORA (largely atosiban) as a tocolytic agent compared with placebo, betamimetics or CCB (largely nifedipine) in terms of pregnancy prolongation or neonatal outcomes, although ORA was associated with less maternal adverse effects than treatment with the CCB or betamimetics. The finding of an increase in infant deaths and more births before completion of 28 weeks of gestation in one placebo-controlled study warrants caution. However, the number of women enrolled at very low gestations was small. Due to limitations of small numbers studied and methodological quality, further well-designed randomised controlled trials are needed. Further comparisons of ORA versus CCB (which has a better side-effect profile than betamimetics) are needed. Consideration of further placebo-controlled studies seems warranted. Future studies of tocolytic agents should measure all important short- and long-term outcomes for women and infants, and costs.
Topics: Albuterol; Female; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Obstetric Labor, Premature; Oligopeptides; Pregnancy; Randomized Controlled Trials as Topic; Receptors, Oxytocin; Ritodrine; Terbutaline; Tocolytic Agents; Vasotocin
PubMed: 24903678
DOI: 10.1002/14651858.CD004452.pub3 -
Annals of Thoracic Medicine Apr 2014The efficacy of magnesium sulphate in chronic obstructive pulmonary disease (COPD) was assessed by conducting a systematic review of published randomized clinical trials...
The efficacy of magnesium sulphate in chronic obstructive pulmonary disease (COPD) was assessed by conducting a systematic review of published randomized clinical trials through extensive searches in MEDLINE and SCOPUS with no date limits, as well as manual review of journals. Outcome measures varied depending on route(s) of administration of magnesium sulphate and medications co-administered. Risk of bias was evaluated and quality of evidence was graded. Four (4) randomized trials were included. All trials had a moderate risk of bias and were of average methodological quality. Magnesium sulphate given intravenously did not seem to have an immediate bronchodilatory effect; however it appears to potentiate the bronchodilatory effect of inhaled beta-2 agonists. Increase in peak expiratory flow rate (PEFR) at 30 and 45 min was greater in those who received magnesium sulphate compared to placebo (P = 0.03), although the mean percentage change in PEFR was just 24%, without significant differences in dyspnoea scores, hospital admission rates, or emergency department readmission rates compared to placebo. Nebulized magnesium sulphate with salbutamol versus nebulized salbutamol with saline placebo showed no significant differences is forced expiratory volume in 1 s (FEV1) measured at 90 min after adjustment for baseline FEV1 (P = 0.34) or differences in the need for hospital admission. Combined inhalational and intravenous magnesium sulphate versus intravenous saline placebo and nebulized ipratropium bromide were comparable in terms of hospital admission, intubation and death, but the ipratropium bromide group showed better bronchodilator effect and improvement in arterial blood gas parameters. Overall, trial evidence for trial evidence for magnesium sulphate in acute exacerbation of COPD is poor, and further well-designed trials are needed.
PubMed: 24791169
DOI: 10.4103/1817-1737.128844 -
The Cochrane Database of Systematic... Feb 2014For adults with asthma that is poorly controlled on inhaled corticosteroids (ICS), guidelines suggest adding a long-acting beta2-agonist (LABA). The LABA can be taken... (Review)
Review
BACKGROUND
For adults with asthma that is poorly controlled on inhaled corticosteroids (ICS), guidelines suggest adding a long-acting beta2-agonist (LABA). The LABA can be taken together with ICS in a single (combination) inhaler. Improved symptom control can be assessed in the individual; however, the long-term risk of hospital admission or death requires evidence from randomised controlled trials. Clinical trials record these safety outcomes as non-fatal and fatal serious adverse events (SAEs), respectively.
OBJECTIVES
To assess the risk of serious adverse events in adults with asthma treated with regular maintenance formoterol or salmeterol compared with placebo, or when randomly assigned in combination with regular ICS, compared with the same dose of ICS.
METHODS
We included Cochrane reviews on the safety of regular formoterol and salmeterol from a June 2013 search of the Cochrane Database of Systematic Reviews. We carried out a search for additional trials in September 2013 and incorporated the new data. All reviews were independently assessed for inclusion and for quality (using the AMSTAR tool). We extracted from each review data from trials recruiting adults (participants older than 12 or 18 years of age).We combined the results from reviews on formoterol and salmeterol to assess the safety of twice-daily regular LABA as a class effect, both as monotherapy versus placebo and as combination therapy versus the same dose of ICS.We did not combine the results of direct and indirect comparisons of formoterol and salmeterol, or carry out a network meta-analysis, because of concerns over transitivity assumptions that posed a threat to the validity of indirect comparisons.
MAIN RESULTS
We identified six high-quality, up-to-date Cochrane reviews. Of these, four reviews (89 trials with 61,366 adults) related to the safety of regular formoterol or salmeterol as monotherapy or combination therapy. Two reviews assessed safety from trials in which adults were randomly assigned to formoterol versus salmeterol. These included three trials with 1116 participants given monotherapy (all prescribed background ICS) and 10 trials with 8498 adults receiving combination therapy. An additional search for trials in September 2013 identified five new included studies contributing data from 693 adults with asthma treated with combination formoterol/fluticasone in comparison with the same dose of inhaled fluticasone, as well as from 447 adults for whom formoterol monotherapy was compared with placebo.No trials reported separate results in adolescents. Overall, risks of bias for the primary outcomes were assessed as low. Death of any causeNone of the reviews found a significant increase in death of any cause from direct comparisons; however, none of the reviews could exclude the possibility of a two-fold increase in mortality on regular formoterol or salmeterol (as monotherapy vs placebo or as combination therapy versus ICS) in adults with asthma. Pooled mortality results from direct comparisons were as follows: formoterol monotherapy (odds ratio (OR) 4.49, 95% confidence interval (CI) 0.24 to 84.80, 13 trials, N = 4824), salmeterol monotherapy (OR 1.33, 95% CI 0.85 to 2.08, 10 trials, N = 29,128), formoterol combination (OR 3.56, 95% CI 0.79 to 16.03, 25 trials, N = 11,271) and salmeterol combination (OR 0.90, 95% CI 0.31 to 2.6, 35 trials, N = 13,447). In each case, we did not detect heterogeneity, and the quality of evidence was rated as moderate. Absolute differences in mortality were very small, translating into an increase of 7 per 10,000 over 26 weeks on any monotherapy (95% CI 2 less to 23 more) and 3 per 10,000 over 32 weeks on any combination therapy (95% CI 3 less to 17 more).Very few deaths were reported in the combination therapy trials, and combination therapy trial designs were different from those of monotherapy trials. Therefore we could not use indirect evidence to assess whether regular combination therapy was safer than regular monotherapy.Only one death occurred in the monotherapy trials comparing formoterol versus salmeterol, so evidence was insufficient to compare mortality. Non-fatal serious adverse events of any causeDirect evidence showed that non-fatal serious adverse events were increased in adults receiving salmeterol monotherapy (OR 1.14, 95% 1.01 to 1.28, I(2) = 0%,13 trials, N = 30,196) but were not significantly increased in any of the other reviews: formoterol monotherapy (OR 1.26, 95% CI 0.78 to 2.04, I(2) = 15%, 17 trials, N = 5758), formoterol combination (OR 0.99, 95% CI 0.77 to 1.27, I(2) = 0%, 25 trials, N = 11,271) and salmeterol combination (OR 1.15, 95% CI 0.91 to 1.44, I(2) = 0%, 35 trials, N = 13,447). This represents an absolute increase on any monotherapy of 43 per 10,000 over 26 weeks (95% CI 6 more to 85 more) and 16 per 10,000 over 32 weeks (95% CI 22 less to 60 more) on any combination therapy.Direct comparisons of formoterol and salmeterol detected no significant differences between risks of all non-fatal events in adults (as monotherapy or as combination therapy).
AUTHORS' CONCLUSIONS
Available evidence from the reviews of randomised trials cannot definitively rule out an increased risk of fatal serious adverse events when regular formoterol or salmeterol was added to an inhaled corticosteroid (as background or as randomly assigned treatment) in adults or adolescents with asthma.An increase in non-fatal serious adverse events of any cause was found with salmeterol monotherapy, and the same increase cannot be ruled out when formoterol or salmeterol was used in combination with an inhaled corticosteroid, although possible increases are small in absolute terms.However, if the addition of formoterol or salmeterol to an inhaled corticosteroid is found to improve symptomatic control, it is safer to give formoterol or salmeterol in the form of a combination inhaler (as recommended by the US Food and Drug Administration (FDA)). This prevents the substitution of LABA for an inhaled corticosteroid if symptom control is improved on LABA.The results of three large ongoing trials in adults and adolescents are awaited; these will provide more information on the safety of combination therapy under less supervised conditions and will report separate results for the adolescents included.
Topics: Adrenergic beta-2 Receptor Agonists; Adult; Albuterol; Asthma; Bronchodilator Agents; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Humans; Randomized Controlled Trials as Topic; Review Literature as Topic; Salmeterol Xinafoate
PubMed: 24504983
DOI: 10.1002/14651858.CD010314.pub2 -
The Cochrane Database of Systematic... Feb 2014Preterm birth is a major contributor to perinatal mortality and morbidity worldwide. Tocolytic agents are drugs used to inhibit uterine contractions. Betamimetics are... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Preterm birth is a major contributor to perinatal mortality and morbidity worldwide. Tocolytic agents are drugs used to inhibit uterine contractions. Betamimetics are tocolytic agents that have been widely used, especially in resource-poor countries.
OBJECTIVES
To assess the effects of betamimetics given to women with preterm labour.
SEARCH METHODS
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2013) and reference lists of retrieved studies.
SELECTION CRITERIA
Randomised controlled trials of betamimetics, administered by any route or any dose, in the treatment of women in preterm labour where betamimetics were compared with other betamimetics, placebo or no treatment.
DATA COLLECTION AND ANALYSIS
Two review authors assessed risk of bias and extracted the data independently.
MAIN RESULTS
Twenty-eight trials were assessed as eligible for inclusion in the review, but eight did not report any outcome data relevant to the review. Results are based on the 20 trials that contributed data.Twelve trials, involving 1367 women, compared betamimetics with placebo. Betamimetics decreased the number of women in preterm labour giving birth within 48 hours (average risk ratio (RR) 0.68, 95% confidence interval (CI) 0.53 to 0.88, 10 trials, 1209 women). There was a decrease in the number of births within seven days (average RR 0.80; 95% CI 0.65 to 0.98, five trials, 911 women) but there was no evidence of a reduction in preterm birth (before 37 weeks' gestation) (RR 0.95; 95% CI 0.88 to 1.03, 10 trials, 1212 women). No benefit was demonstrated for betamimetics for perinatal death (RR 0.84; 95% CI 0.46 to 1.55, 11 trials, 1332 infants), or neonatal death (RR 0.90; 95% CI 0.27 to 3.00, six trials, 1174 infants). No significant effect was demonstrated for respiratory distress syndrome (RR 0.87; 95% CI 0.71 to 1.08, eight trials, 1239 infants). A few trials reported on cerebral palsy, infant death and necrotising enterocolitis; no significant differences between groups were identified for any of these outcomes. Betamimetics were significantly associated with the following outcomes: withdrawal from treatment due to adverse effects; maternal chest pain; dyspnoea; palpitation; tremor; headaches; hypokalaemia; hyperglycaemia; nausea or vomiting; nasal stuffiness; and fetal tachycardia.Nine trials compared different types of betamimetics. Other betamimetics were compared with ritodrine in five trials (n = 948). Other comparisons were examined in single trials: hexoprenaline compared with salbutamol (n = 140), slow versus moderate release salbutamol (n = 52) and salbutamol compared with terbutaline (n = 200). Trials were small, varied, and of insufficient quality to delineate any consistent patterns of effect.
AUTHORS' CONCLUSIONS
Betamimetics help to delay birth, which may give time to allow women to be transferred to tertiary care or to complete a course of antenatal corticosteroids. However, multiple adverse effects must be considered. The data are too few to support the use of any particular betamimetic.
Topics: Adrenergic beta-Agonists; Female; Fenoterol; Hexoprenaline; Humans; Obstetric Labor, Premature; Pregnancy; Premature Birth; Randomized Controlled Trials as Topic; Ritodrine; Terbutaline; Tocolytic Agents
PubMed: 24500892
DOI: 10.1002/14651858.CD004352.pub3 -
Respiratory Care Oct 2013Evidence-based medicine (EBM) is the integration of individual clinical expertise with the best available research evidence from systematic research and the patient's... (Meta-Analysis)
Meta-Analysis Review
Evidence-based medicine (EBM) is the integration of individual clinical expertise with the best available research evidence from systematic research and the patient's values and expectations. A hierarchy of evidence can be used to assess the strength upon which clinical decisions are made. The efficient approach to finding the best evidence is to identify systematic reviews or evidence-based clinical practice guidelines. Respiratory therapies that evidence supports include noninvasive ventilation for appropriately selected patients, lung-protective ventilation, and ventilator discontinuation protocols. Evidence does not support use of weaning parameters, albuterol for ARDS, and high frequency oscillatory ventilation for adults. Therapy with equivocal evidence includes airway clearance, selection of an aerosol delivery device, and PEEP for ARDS. Although all tenets of EBM are not universally accepted, the principles of EBM nonetheless provide a valuable approach to respiratory care practice.
Topics: Biomedical Research; Evidence-Based Medicine; High-Frequency Ventilation; Humans; Practice Guidelines as Topic; Pulmonary Medicine
PubMed: 24064624
DOI: 10.4187/respcare.02591 -
The Cochrane Database of Systematic... Aug 2013Both long-acting beta(2)-agonists and inhaled corticosteroids have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease (COPD).... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Both long-acting beta(2)-agonists and inhaled corticosteroids have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease (COPD). Their co-administration in a combined inhaler is intended to facilitate adherence to medication regimens and to improve efficacy. Three preparations are currently available: fluticasone propionate/salmeterol (FPS). budesonide/formoterol (BDF) and mometasone furoate/formoterol (MF/F).
OBJECTIVES
To assess the efficacy and safety of combined long-acting beta2-agonist and inhaled corticosteroid (LABA/ICS) preparations, as measured by clinical endpoints and pulmonary function testing, compared with inhaled corticosteroids (ICS) alone, in the treatment of adults with chronic obstructive pulmonary disease (COPD).
SEARCH METHODS
We searched the Cochrane Airways Group Specialised Register of trials, which is compiled from systematic searches of multiple literature databases. The search was conducted in June 2013. In addition, we checked the reference lists of included studies and contacted the relevant manufacturers.
SELECTION CRITERIA
Studies were included if they were randomised and double-blind. Compared studies combined LABA/ICS with the ICS component.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trial quality and extracted data. The primary outcomes were exacerbations, mortality and pneumonia. Health-related quality of life (as measured by validated scales), lung function and side effects were secondary outcomes. Dichotomous data were analysed as fixed-effect odds ratios with 95% confidence intervals (CIs), and continuous data as mean differences or rate ratios and 95% CIs.
MAIN RESULTS
A total of 15 studies of good methodological quality met the inclusion criteria by randomly assigning 7814 participants with predominantly poorly reversible, severe COPD. Data were most plentiful for the FPS combination. Exacerbation rates were significantly reduced with combination therapies (rate ratio 0.87, 95% CI 0.80 to 0.94, 6 studies, N = 5601) compared with ICS alone. The mean exacerbation rate in the control (ICS) arms of the six included studies was 1.21 exacerbations per participant per year (range 0.88 to 1.60), and we would expect this to be reduced to a rate of 1.05 (95% CI 0.97 to 1.14) among those given combination therapy. Mortality was also lower with the combination (odds ratio (OR) 0.78, 95% CI 0.64 to 0.94, 12 studies, N = 7518) than with ICS alone, but this was heavily weighted by a three-year study of FPS. When this study was removed, no significant mortality difference was noted. The reduction in exacerbations did not translate into significantly reduced rates of hospitalisation due to COPD exacerbation (OR 0.93, 95% CI 0.80 to 1.07, 10 studies, N = 7060). Lung function data favoured combination treatment in the FPS, BDF and MF/F trials, but the improvement was small. Small improvements in health-related quality of life were measured on the St George's Respiratory Questionnaire (SGRQ) with FPS or BDF compared with ICS, but this was well below the minimum clinically important difference. Adverse event profiles were similar between the two treatments arms, and rates of pneumonia when it was diagnosed by chest x-ray (CXR) were lower than those reported in earlier trials.
AUTHORS' CONCLUSIONS
Combination ICS and LABA offer some clinical benefits in COPD compared with ICS alone, especially for reduction in exacerbations. This review does not support the use of ICS alone when LABAs are available. Adverse events were not significantly different between treatments. Further long-term assessments using practical outcomes of current and new 24-hour LABAs will help determine their efficacy and safety. For robust comparisons as to their relative effects, long-term head-to-head comparisons are needed.
Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Humans; Nebulizers and Vaporizers; Pneumonia; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Steroids
PubMed: 23990350
DOI: 10.1002/14651858.CD006826.pub2