Anticholinergics for asthma: a long history.

PURPOSE OF REVIEW: To provide a fast overview about the introduction and development of anticholinergic drugs in Western medicine to their current indications particularly in asthma. RECENT FINDINGS: Although short-acting muscarinic antagonists have been positioned in the last 15 years for the treatment of adults and children with moderate-to-severe acute asthma in the emergency setting (reducing the risk of hospital admissions and improving lung function), a growing body of evidence has recently emerged that positions the long-acting muscarinic anticholinergic tiotropium bromide as add-on therapy to at least inhaled corticosteroids (ICS) maintenance therapy in adults, adolescents, and children with symptomatic asthma. Thus, the addition of tiotropium bromide to ICS alone or ICS and another controller was associated with significant improvements in spirometric measures and asthma control, and a significantly decrease in the rate of asthma exacerbations. SUMMARY: Short-acting muscarinic antagonists and tiotropium bromide have a well established role in the treatment of different phases of asthma. Further data are needed to provide more evidence on other selective long-acting muscarinic antagonists in addition to tiotropium as potential treatment options.

Efficacy and safety of tiotropium in school-age children with moderate-to-severe symptomatic asthma: A systematic review.

BACKGROUND: Recently published data support the benefits and safety of the once-daily (OD) long-acting anticholinergic tiotropium bromide bronchodilator for the treatment of uncontrolled moderate-to-severe asthma in adults and adolescents. However, its role for the treatment of school-age asthmatics has not yet been clearly defined. The aim of this systematic review was to assess the efficacy and safety of tiotropium Respimat® in children aged 6-11 years with moderate-to-severe symptomatic asthma. METHODS: Randomized, placebo-controlled trials were included. Primary outcomes were peak forced expiratory volume in 1 s measured within 3 h post-dosing) [FEV1 (0-3 h) ] and trough FEV1 measured at the end of the dosing interval. RESULTS: Three studies (more than 900 patients) were selected. Tiotropium was associated with significant improvements in FEV1 peak (mean change from baseline) by 102 mL (P<.0001) and trough by 82 mL (P<.0001) compared with placebo. Tiotropium 5 µg dose presented a trend (statistically non-significant) toward a greater bronchodilation in comparison with 2.5 µg dose. Tiotropium significantly increased the rate of the Asthma Control Questionnaire (ACQ-7) responders compared with placebo (82.2% vs 75.4%, number needed to treat for benefit [NNTB]=15) and significantly decreased the number of patients with at least one exacerbation in comparison with placebo (29.1% vs. 39.8%, with a NNTB of 10). There were no significant differences in rescue medication use, withdrawals, and adverse events. CONCLUSIONS: OD tiotropium Respimat® is efficacious and well tolerated as an add-on to inhaled corticosteroids plus one or more controller medications in school-age symptomatic asthmatics.

LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis.

BACKGROUND: Randomized controlled trials (RCTs) indicate that long-acting bronchodilator combinations, such as ß2-agonist (LABA)/muscarinic antagonist (LAMA), have favorable efficacy compared with commonly used COPD treatments. The objective of this analysis was to compare the efficacy and safety of LABA/LAMA with LAMA or LABA/inhaled corticosteroid (ICS) in adults with stable moderate-to-very-severe COPD. METHODS: This systematic review and meta-analysis (PubMed/MEDLINE, Embase, Cochrane Library and clinical trial/manufacturer databases) included RCTs comparing ≥12 weeks' LABA/LAMA treatment with LAMA and/or LABA/ICS (approved doses only). Eligible studies were independently selected by two authors using predefined data fields; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. RESULTS: Eighteen studies (23 trials) were eligible (N=20,185). LABA/LAMA significantly improved trough forced expiratory volume in 1 second (FEV1) from baseline to week 12 versus both LAMA and LABA/ICS (0.07 L and 0.08 L, P<0.0001), with patients more likely to achieve clinically important improvements in FEV1 of >100 mL (risk ratio [RR]: 1.33, 95% confidence interval [CI]: [1.20, 1.46] and RR: 1.44, 95% CI: [1.33, 1.56], respectively, the number needed to treat being eight and six, respectively). LABA/LAMA improved transitional dyspnea index and St George's Respiratory Questionnaire scores at week 12 versus LAMA (both P<0.0001), but not versus LABA/ICS, and reduced rescue medication use versus both (P<0.0001 and P=0.001, respectively). LABA/LAMA significantly reduced moderate/severe exacerbation rate compared with LABA/ICS (RR 0.82, 95% CI: [0.75, 0.91]). Adverse event (AE) incidence was no different for LABA/LAMA versus LAMA treatment, but it was lower versus LABA/ICS (RR 0.94, 95% CI: [0.89, 0.99]), including a lower pneumonia risk (RR 0.59, 95% CI: [0.43, 0.81]). LABA/LAMA presented a lower risk for withdrawals due to lack of efficacy versus LAMA (RR: 0.66, 95% CI: [0.51, 0.87]) and due to AEs versus LABA/ICS (RR: 0.83, 95% CI: [0.69, 0.99]). CONCLUSION: The greater efficacy and comparable safety profiles observed with LABA/LAMA combinations versus LAMA or LABA/ICS support their potential role as first-line treatment options in COPD. These findings are of direct relevance to clinical practice because we included all currently available LABA/LAMAs and comparators, only at doses approved for clinical use.

Systematic review on the use of omalizumab for the treatment of asthmatic children and adolescents.

BACKGROUND: There are less data on omalizumab treatment in pediatric asthma than in adult population. Thus, to establish the efficacy and safety of subcutaneous omalizumab as an add-on therapy, a systematic review of placebo-controlled studies was performed. METHODS: Primary outcome was the frequency of asthma exacerbations. Secondary outcomes included spirometric measures, rescue medication use, asthma symptoms, health-related quality of life, and adverse events. RESULTS: Three randomized controlled trials (1381 participants) fulfilled the selection criteria. During the stable phase, omalizumab decreased the number of patients with at least one significant asthma exacerbation (26.7% vs. 40.6%, NNTB = 7, 95% CI, 5, 11). The predefined post hoc subgroup analysis showed that duration of treatment did not influence this result. During the steroid reduction phase, omalizumab reduced the number of patients with at least one exacerbation (RR = 0.48, 95% CI, 0.38, 0.61; NNTB = 6, 95% CI, 4, 8) and also the mean number of asthma exacerbations per patient (MD = -0.44, 95% CI, -0.72, -0.17) when compared to placebo. The frequency of serious adverse events was similar between omalizumab (5.2%) and placebo (5.6%), and there were no evidence of increased risk of hypersensitivity reactions, nor malignant neoplasms. CONCLUSIONS: Data indicate that the efficacy of an add-on omalizumab in patients with moderate-to-severe allergic asthma uncontrolled with recommended inhaled steroid treatment is accompanied by an acceptable safety profile.

Advances in acute asthma.

PURPOSE OF REVIEW: The purpose of this study is to highlight some of the recent findings related with the management of acute exacerbations in the context of the emergency department setting. RECENT FINDINGS: ß2-agonist heliox-driven nebulization significantly increased by 17% [95% confidence interval (CI) 5.2-29.4] peak expiratory flow, and decreased the rate of hospital admissions (risk ratio 0.77, 95% CI 0.62-0.98), compared with oxygen-driven nebulization. Other findings indicate that there is no robust evidence to support the use of intravenous or nebulized magnesium sulphate in adults with severe acute asthma, and that levalbuterol was not superior to albuterol regarding efficacy and safety in individuals with acute asthma. Finally, hyperlactatemia developed during the first hours of acute asthma treatment has a high prevalence, is related with the use of ß2-agonists and had no clinical consequences. SUMMARY: After a comprehensive review of the best quality pieces of literature published in the last year, it is possible to conclude that the goals of acute asthma management remain almost unchanged.

Principal findings of systematic reviews for chronic treatment in childhood asthma.

OBJECTIVE: To summarize the principal findings pertaining to most effective long-term pharmacologic treatment of childhood asthma. METHODS: Systematic reviews of randomized clinical trials (SRCTs) on pharmacologic chronic treatment in children (1-18 years) with persistent asthma were retrieved through MEDLINE, EMBASE, CINAHL, SCOPUS, and CDSR (up to January2014). RESULTS: One hundred eighty-three SRCTs were searched from databases. Among those, 39 SRCTs were included: two were related to step 1, 24 to step 2, nine to steps 3 and 4, and four to step 5 (according with NAEPP and GINA guidelines). The methodological quality of these SRCTs was determined by using the AMSTAR tool. RESULTS: For step 1: addition of ipatropium bromide to short-acting beta2-agonists does not show any benefit. For step 2: in preschoolers, inhaled corticosteroids (ICSs) reduce severe exacerbations and improve other clinical and lung function parameters. In children, ICSs are superior to leukotriene receptor antagonist (LTRA), cromones, or xantines in reducing severe exacerbations, improving lung function and other clinical outcomes. Fluticasone propionate (FP) is better than beclomethasone dipropionate (BDP) or budesonide only for lung function; but similar to hydrofluoroalkane-BDP or to ciclosenide. Compared to low ICSs doses, moderate doses result in only better lung function, but this is not true for FP. For steps 3 and 4: adding LTRA to ICS confers a small benefit; adding LABA improves lung function but does not reduce exacerbations more than double or higher ICS doses. For step 5: adding omalizumab decreases exacerbations. CONCLUSIONS: SRCTs are useful for guiding decisions in chronic childhood asthma treatment.

Asthma in the elderly: what we know and what we have yet to know.

In the past, asthma was considered mainly as a childhood disease. However, asthma is an important cause of morbidity and mortality in the elderly nowadays. In addition, the burden of asthma is more significant in the elderly than in their younger counterparts, particularly with regard to mortality, hospitalization, medical costs or health-related quality of life. Nevertheless, asthma in the elderly is still been underdiagnosed and undertreated. Therefore, it is an imperative task to recognize our current challenges and to set future directions. This project aims to review the current literature and identify unmet needs in the fields of research and practice for asthma in the elderly. This will enable us to find new research directions, propose new therapeutic strategies, and ultimately improve outcomes for elderly people with asthma. There are data to suggest that asthma in older adults is phenotypically different from young patients, with potential impact on the diagnosis, assessment and management in this population. The diagnosis of AIE in older populations relies on the same clinical findings and diagnostic tests used in younger populations, but the interpretation of the clinical data is more difficult. The challenge today is to encourage new research in AIE but to use the existing knowledge we have to make the diagnosis of AIE, educate the patient, develop a therapeutic approach to control the disease, and ultimately provide a better quality of life to our elderly patients.

Daily versus intermittent inhaled corticosteroid treatment for mild persistent asthma.

PURPOSE OF REVIEW: Guidelines recommend the use of daily inhaled corticosteroids as preferred treatment for preschoolers, children, adolescents, and adults with recurrent wheezing and mild persistent asthma. However, intermittent or as-needed inhaled corticosteroids treatment in response to symptoms is an emerging strategy. This review is focused on the analysis (clinical efficacy and safety) of this approach in comparison with the current daily-based therapy. RECENT FINDINGS: Recently, some authors favored the use of inhaled corticosteroids based on symptoms. It has been suggested that a symptom-based approach could reduce the amount of drug used, minimize the risk of adverse events, and reduce healthcare costs. In contrast, physicians prescribing intermittent inhaled corticosteroids would give the wrong message to their patients about the chronicity of the disease. Currently, there is a significant body of high-quality clinical studies and systematic reviews that have addressed this important controversy, and whose analysis allows us to extract some important conclusions. SUMMARY: Present evidence does not support a change in the direction of an intermittent or symptom-based use approach for recurrent wheezing and mild-to-moderate persistent asthma. At this point, there is no convincing basis to alter the current strategy to inhaled corticosteroids dosing, and more studies are needed comparing these two approaches.

Daily vs. intermittent inhaled corticosteroids for recurrent wheezing and mild persistent asthma: a systematic review with meta-analysis.

BACKGROUND: Intermittent ICS treatment with SABA in response to symptoms, is an emerging strategy for control of mild-to-moderate asthma, and recurrent wheezing. This systematic revue compares the efficacy of daily vs. intermittent ICS among preschoolers, children and adults with persistent wheezing and mild to moderate stable persistent asthma. METHODS: Systematic review of randomized, placebo-controlled trials with a minimum of 8 weeks of daily (daily ICS with rescue SABA during exacerbations) vs. intermittent ICS (ICS plus SABA at the onset of symptoms), were retrieved through different databases. Primary outcome was asthma exacerbations; secondary outcomes were pulmonary function tests, symptoms, days without symptoms, SABA use, corticosteroids use, days without rescue medication use, expired nitric oxide and serious adverse events. RESULTS: Seven trials (1367 participants) met inclusion criteria there was no statistically significant difference in the rate of asthma exacerbations between those with daily vs. intermittent ICS (0.96; 95% CI: 0.86, 1.06, I(2) = 0%). In the sub-group analysis, no differences were seen in duration of studies, step-up strategy or age. However, compared to intermittent ICS, the daily ICS group had a significant increase in asthma-free days and non-significant decreases in rescue SABA use and exhaled nitric oxide measurement. CONCLUSIONS: No significant differences between daily and intermittent ICS in reducing the incidence of asthma exacerbations was found. However, the daily ICS strategy was superior in many secondary outcomes. Therefore, this study suggests to not change daily for intermittent ICS use among preschoolers, children with persistent wheezing and adults with mild-to-moderate stable persistent asthma. International prospective register of systematic reviews http://www.crd.york.ac.uk/PROSPERO/ (CRD42012003228).

A systematic review of long-acting ß2-agonists versus higher doses of inhaled corticosteroids in asthma.

OBJECTIVE: To compare the efficacy of inhaled corticosteroids (ICS) plus long-acting ß2 agonist (LABA) versus higher doses of ICS in children/adolescents with uncontrolled persistent asthma. METHODS: Randomized, prospective, controlled trials published January 1996 to January 2012 with a minimum of 4 weeks of LABA+ICS versus higher doses of ICS were retrieved through Medline, Embase, Central, and manufacturer's databases. The primary outcome was asthma exacerbations requiring systemic corticosteroids; secondary outcomes were the pulmonary function test (PEF), withdrawals during the treatment period, days without symptoms, use of rescue medication, and adverse events. RESULTS: Nine studies (n = 1641 patients) met criteria for inclusion (7 compared LABA+ICS versus double ICS doses and 2 LABA+ICS versus higher than double ICS doses). There was no statistically significant difference in the number of patients with asthma exacerbations requiring systemic corticosteroids between children receiving LABA+ICS and those receiving higher doses of ICS (odds ratio = 0.76; 95% confidence interval: 0.48-1.22, P = .25, I(2) = 16%). In the subgroup analysis, patients receiving LABA+ICS showed a decreased risk of asthma exacerbations compared with higher than twice ICS doses (odds ratio = 0.48; 95% confidence interval: 0.28-0.82, P = .007, I(2)= 0). Children treated with LABA+ICS had significantly higher PEF, less use of rescue medication, and higher short-term growth than those on higher ICS doses. There were no other significant differences in adverse events. CONCLUSIONS: There were no statistically significant group differences between ICS+LABA and double doses of ICS in reducing the incidence of asthma exacerbations but it did decrease the risk comparing to higher than double doses of ICS.

Comparison of three combined pharmacological approaches with tiotropium monotherapy in stable moderate to severe COPD: a systematic review.

BACKGROUND: Guidelines recommend the use of inhaled long-acting bronchodilators, inhaled corticosteroids (ICS) and their combinations for maintenance treatment of moderate to severe COPD. However, there are limited data supporting combination therapy. METHODS: This systematic review assessed the efficacy of three therapeutic approaches: tiotropium plus long-acting beta2-agonist (LABA) ("dual" therapy), LABA/ICS ("combined" therapy), and tiotropium plus LABA/ICS ("triple" therapy), all compared with tiotropium monotherapy. Randomized controlled trials were identified after a search of different databases of published and unpublished trials. RESULTS: Twenty trials (6803 participants) were included. "Dual" therapy showed significant improvements in forced volume in the first second (FEV(1)), health-related quality of life (HRQoL), and dyspnea. However, it failed to reduce the risk of COPD exacerbations. Compared with tiotropium, "combined" therapy presented modest but significant effects on FEV(1), HRQoL, and dyspnea. Again, there was no significant difference in exacerbations, but it was associated with a significant increase of serious adverse effects (SAE) (number need to treat for harm [NNTH] = 20; 95% CI: 11-119). Finally, "triple therapy" increased FEV(1), improved HRQoL (both benefits exceeded minimal important differences) and decrease COPD exacerbations in anon-significant way. (Odds ratio [OR] = 0.57; 95% CI: 0.24 to 1.37, p = 0.21). CONCLUSIONS: "Dual" and "triple" therapy seem like the most promising for patients with moderate to very severe COPD. However, data are still scarce and studies too short to generate a strong recommendation. Future studies should examine long-term efficacy and safety.

Safety of long-acting ß agonists for the treatment of asthma: clearing the air.

Concerns about the safety of long-acting ß2-agonist (LABA) therapy, has led to the appearance of multiple publications and recommendations. This review critically examines the available clinical evidence and safety requirements for LABA use. On the basis of nearly 20 systematic reviews and databases, the authors conclude that LABA monotherapy significantly increases the risk of asthma-related adverse effects. We also conclude that the use of LABAs concomitantly with inhaled corticosteroids (ICS) significantly reduces asthma hospitalisations and is not associated with life-threatening events and asthma-related deaths, especially when concurrent use of LABAs and ICS can be reasonably assured (use of a single inhaler device). An appropriate clinical study would require an extremely large sample, making it impractical. Finally, some of the new US Food and Drug Administration (FDA) recommendations have caused confusion and do not appear to be fully evidence based. Although limited by low statistical power, the evidence supports the use of LABAs plus ICS in a single inhaler device (to increase adherence and reduce the potential use of LABA monotherapy) for all patients (not only children) with moderate to severe asthma.

Efficacy and safety of subcutaneous omalizumab vs placebo as add-on therapy to corticosteroids for children and adults with asthma: a systematic review.

BACKGROUND: Omalizumab is a humanized monoclonal anti-IgE for the treatment of severe allergic asthma. Because omalizumab targets an immune system molecule, there has been particular interest in the drug's safety. METHODS: To establish the efficacy and safety of subcutaneous omalizumab as add-on therapy to corticosteroids, a systematic review of placebo-controlled studies was performed. Primary outcomes were reduction of steroid use and asthma exacerbations. Secondary outcome measures included lung function, rescue medication use, asthma symptoms, health-related quality of life, and adverse effects. RESULTS: Eight trials (3,429 participants) fulfilled the selection criteria. At the end of the steroid-reduction phase, patients taking omalizumab were more likely to be able to withdraw from corticosteroids completely compared with those taking placebo (relative risk [RR] = 1.80; 95% CI, 1.42-2.28; P = .00001). Omalizumab patients showed a decreased risk of asthma exacerbations at the end of the stable (RR = 0.57; 95% CI, 0.48-0.66; P = .0001) and adjustable-steroid phases (RR = 0.55; 95% CI, 0.47-0.64; P = .0001); post-hoc analysis suggests this effect was independent of duration of treatment, age, severity of asthma, and risk of bias. The frequency of serious adverse effects was similar in the omalizumab (3.8%) and placebo (5.3%) groups. However, injection site reactions were more frequent in the omalizumab patients (19.9% vs 13.2%). There were no indications of increased risk of hypersensitivity reactions, cardiovascular effects, or malignant neoplasms. CONCLUSIONS: Data indicate that the efficacy of add-on omalizumab in patients with moderate-to-severe allergic asthma is accompanied by an acceptable safety profile.

Formoterol for acute asthma in the emergency department: a systematic review with meta-analysis.

BACKGROUND: Although several published studies have suggested that formoterol fumarate could be equivalent to short-acting beta2-agonists (SABAs) for the treatment of asthma exacerbations, its role in acute asthma treatment remains undefined. OBJECTIVE: To evaluate the efficacy and safety of inhaled formoterol (compared with SABAs) for the emergency department treatment of patients with acute asthma. METHODS: Systematic searches were conducted in MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and manufactures' trial registers, without language restriction. The primary outcomes were spirometric measures. The secondary outcomes included final serum potassium level, heart rate, electrocardiographic QT interval corrected for heart rate, and total withdrawals. RESULTS: Nine randomized controlled trials (including 576 participants) were selected. No significant difference could be detected between formoterol and SABAs for any of the selected time points: at 30 to 40 minutes after the first administration of study drugs (standardized mean difference, -0.19; 95% confidence interval, -0.56 to 0.17; I2 = 75%), at the end of treatment (standardized mean difference, -0.25; 95% confidence interval, -0.72 to 0.13; I2 = 89%), and at 60 to 90 minutes after the last dose (standardized mean difference, -0.13; 95% confidence interval, -0.55 to 0.28; I2 = 80%). Similarly, there were no significant differences between formoterol and SABAs regarding final serum potassium level, heart rate, QT interval, hospitalization rate, and total withdrawals. CONCLUSIONS: This review suggests that high-dose formoterol administered via dry powder inhaler is well tolerated and provides rapid and effective bronchodilation, similar to high-dose salbutamol or terbutaline via metered-dose inhaler or nebulizer. Formoterol may be used in the treatment of acute asthma in the emergency department setting.

The role of inhaled corticosteroids and montelukast in children with mild-moderate asthma: results of a systematic review with meta-analysis.

OBJECTIVE: To compare the efficacy of inhaled corticosteroids (ICS) versus montelukast (MONT) in schoolchildren and adolescents with mild-moderate persistent asthma. METHODS: Randomised, prospective, controlled trials published January 1996 to November 2009 with a minimum of 4 weeks of ICS versus MONT and of ICS versus MONT+ICS were retrieved through Medline, Embase and Central databases. The primary outcome was asthma exacerbations requiring systemic corticosteroids (AEX); secondary outcomes were pulmonary function, withdrawal/hospitalisation due to AEX, change in symptoms score, rescue-medication-free days, albuterol use, adverse effects and adherence. RESULTS: Of 124 studies identified, 18 studies (n=3757 patients) met criteria for inclusion (13 compared ICS vs MONT, 3 ICS vs MONT+ICS and 2 ICS vs MONT vs ICS+MONT). Patients receiving ICS showed a significantly lower risk for AEX than those with MONT (RR=0.83, 95% CI 0.72 to 0.96, p=0.01); post-hoc analysis suggests this effect was independent of quality, sponsorship and study duration. Children treated with ICS had a significant higher pulmonary function (final FEV1 % predicted, change from baseline FEV1 %, final morning peak expiratory flow (PEF)) and better clinical parameters (albuterol use, symptom score, rescue-medication-free days, withdrawals due to AEX) versus MONT. No significant difference in primary or secondary outcomes was found when MONT was added on to ICS versus ICS alone; however, these analyses were based on only two studies. CONCLUSIONS: Schoolchildren and adolescents with mild-moderate persistent asthma treated with ICS had less AEX and better lung function and asthma control than with MONT. There are insufficient data to determine whether the addition of MONT to ICS improves outcome.