Asthma-related Events Research Articles

Cochrane review: Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events

AbstractBackgroundEpidemiological evidence has suggested a link between beta2‐agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long‐acting beta2‐agonists are safe when used alone or in conjunction with inhaled corticosteroids.ObjectivesThe aim of this review is to assess the risk of fatal and non‐fatal serious adverse events in trials that randomised patients with chronic asthma to regular formoterol with inhaled corticosteroids versus the same dose of inhaled corticosteroids alone.Search strategyTrials were identified using the Cochrane Airways Group Specialised Register of trials. Web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol were also checked. The date of the most recent search was October 2008.Selection criteriaControlled parallel design clinical trials on patients of any age and severity of asthma were included if they randomised patients to treatment with regular formoterol and inhaled corticosteroids, and were of at least 12 weeks duration.Data collection and analysisTwo authors independently selected trials for inclusion in the review. Outcome data were independently extracted by two authors. Unpublished data on mortality and serious adverse events were obtained from the sponsors.Main resultsThe review included 14 studies on adults and adolescents (8,028 participants) and seven studies on children and adolescents (2,788 participants). Data on all cause fatal and non‐fatal serious adverse events were found for all studies, and the overall risk of bias was low.Four deaths occurred on regular formoterol with inhaled corticosteroids, and none on regular inhaled corticosteroids alone. All the deaths were in adults, and one was reported to be asthma‐related. The difference was not statistically significant.Non‐fatal serious adverse events of any cause were very similar in adults [Peto Odds Ratio 0.99 (95% CI 0.74 to 1.33)], and an increase in events in children on regular formoterol was not statistically significant [Peto Odds Ratio 1.62 (95% CI 0.80 to 3.28)].Asthma related serious adverse events on formoterol were lower in adults [Peto Odds Ratio 0.53 (95% CI 0.28 to 1.00)] and although they were higher in children [Peto Odds Ratio 1.49 (95% CI 0.48 to 4.61)], this was not statistically significant.Authors' conclusionsIt is not possible, from the data in this review, to reassure people with asthma that inhaled corticosteroids with regular formoterol carries no risk of increasing mortality in comparison to inhaled corticosteroids alone as all four deaths occurred among 6,594 people using inhaled corticosteroids with formoterol. On the other hand, we have found no conclusive evidence of harm and there was only one asthma related death registered during over 3,000 patient year observation on formoterol. In adults, the decrease in asthma‐related serious adverse events on regular formoterol with inhaled corticosteroids was not accompanied by a decrease in all cause serious adverse events. In children the number of events was too small, and consequently the results too imprecise, to determine whether the increase in all cause non‐fatal serious adverse events found in the previous meta‐analysis on regular formoterol alone is abolished by the additional use of inhaled corticosteroids. Clinical decisions and information for patients regarding regular use of formoterol have to take into account the balance between known symptomatic benefits of formoterol and the degree of uncertainty and concern associated with its potential harmful effects.Plain Language SummarySerious adverse events with regular formoterol and inhaled corticosteroidsThere has been some concern raised at the possibility of increased serious adverse events following administration of formoterol, a long‐acting beta‐agonist, to people with asthma. We analysed data from 14 studies in adults and seven in children. Too few deaths occurred in the trials to gain any conclusive reassurance that regular formoterol taken with inhaled corticosteroids either reduces the risk of mortality, or in fact does not increase it (all four deaths that did occur, including one related to asthma, were among 6,594 patients taking formoterol with inhaled corticosteroids). Serious adverse events were very similar in adults with and without formoterol. Although there were more events on formoterol in children, the difference was not big enough to rule out this as being a chance finding. Similarly, decreased risk of asthma‐related serious adverse events in adults and increased risk among children taking formoterol could be also be chance findings.

Efficacy of probiotic Lactobacillus GG on allergic sensitization and asthma in infants at risk

Probiotics are perceived to exert beneficial effects in the prevention and treatment of allergic diseases. There are conflicting data from studies as to an impact on allergic sensitization and asthma. Our prospective double-blind study randomly assigned 131 children (6-24 months old) with at least two wheezing episodes and a first-degree family history of atopic disease to 6 months of Lactobacillus rhamnosus (LGG, 10(10) colony forming units) or placebo. Atopic dermatitis and asthma-related events (e.g. need of inhalation, symptom-free days) were documented throughout the intervention and 6-month follow-up. We determined IgE, a representative panel of specific IgE, eosinophils, eosinophilic cationic protein, and TGF-beta before, at the end of intervention, and after 6 months of follow-up. There were no significant differences as to atopic dermatitis or asthma-related events. In a subgroup with antecedent allergic sensitizations, asthmatic complaints were even slightly worse. We found fewer sensitizations towards aeroallergens after 6 months of LGG (P=0.027) and after 6 months of follow-up (P=0.03). Supplementation was well-tolerated and no severe adverse events occurred. In young children with recurrent wheeze and an atopic family history, oral LGG had no clinical effect on atopic dermatitis or asthma-related events, and only mild effects on allergic sensitization. This effect persisted 6 months after the cessation of the supplementation.

Italian real-life experience of omalizumab

Omalizumab is a humanized murine monoclonal antibody directed toward a portion of the IgE indicated in Europe for the treatment of severe persistent allergic asthma, inadequately controlled despite high-dose of ICS (mean BDP equivalent dose of inhaled corticosteroid 2224.68microg/die) in association with long-acting beta(2) agonists. Our aim was to describe the experience, efficacy and safety in a cohort of Italian patients treated with omalizumab in a real-life clinical setting. One hundred and forty two patients from 13 Italian Centers were observed and analysed. The dosage of omalizumab was established according to the labelling indication, with a median dose of IgE of 297.38IU/ml or kU/l. During the previous year, all patients experienced frequent exacerbations (mean=4.87), emergency visits (mean=4.45) and hospitalisation (mean=1.53). Following treatment with omalizumab, the annual rate of exacerbations, emergency visits and hospitalisation decreased by 79%, 88% and 95%, respectively. The proportion of patients without exacerbation, not needing emergency visits and hospitalization increased by 610%, 154% and 28%, respectively. The response to omalizumab measured with the GETE (global evaluation of treatment effectiveness) scale rated as good to excellent in 77% of patients. Overall, 9.6% (n=9) of the patients experienced one single adverse effect. Only one patient reported a serious adverse event (local reaction at the site of injection) leading to interruption of treatment. The observed reduction of asthma-related events in particularly poorly controlled patients in this Italian real-life setting is consistent with the results of other observational studies.

Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events

An increase in serious adverse events with both regular formoterol and regular salmeterol in chronic asthma has been demonstrated in comparison with placebo in previous Cochrane reviews. This increase was significant in trials that did not randomise participants to an inhaled corticosteroid, but less certain in the smaller numbers of participants in trials that included an inhaled corticosteroid in the randomised treatment regimen. We set out to compare the risks of mortality and non-fatal serious adverse events in trials which have randomised patients with chronic asthma to regular formoterol versus regular salmeterol, when each are used with an inhaled corticosteroid as part of the randomised treatment. Trials were identified using the Cochrane Airways Group Specialised Register of trials. Manufacturers' web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol were also checked. The date of the most recent search was July 2009. Controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma were included if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid), and were of at least 12 weeks duration. Two authors independently selected trials for inclusion in the review and extracted outcome data. Unpublished data on mortality and serious adverse events were sought from the sponsors and authors. Eight studies met the eligibility criteria of the review recruiting 6,163 adults and adolescents. There were seven studies (involving 5,935 adults and adolescents) comparing formoterol and budesonide to salmeterol and fluticasone. All but one study administered the products as a combined inhaler, and most used formoterol 50 mcg and budesonide 400 mcg twice daily versus salmeterol 50 mcg and fluticasone 250 mcg twice daily. There were two deaths overall (one on each combination) and neither were thought to be related to asthma.There was no significant difference between treatment groups for non-fatal serious adverse events, either all-cause (Peto OR 1.14; 95% CI 0.82 to 1.59, I(2) = 26%) or asthma-related (Peto OR 0.69; 95% CI 0.37 to 1.26, I(2) = 33%). Over 23 weeks the rates for all-cause serious adverse events were 2.6% on formoterol and budesonide and 2.3% on salmeterol and fluticasone, and for asthma-related serious adverse events, 0.6% and 0.8% respectively.There was one study (228 adults) comparing formoterol and beclomethasone to salmeterol and fluticasone, but there were no deaths or hospital admissions.No studies were found in children. The seven identified studies in adults did not show any significant difference in safety between formoterol and budesonide in comparison with salmeterol and fluticasone. Asthma-related serious adverse events were rare, and there were no reported asthma-related deaths. There was a single small study comparing formoterol and beclomethasone to salmeterol and fluticasone in adults, but no serious adverse events occurred in this study. No studies were found in children.Overall there is insufficient evidence to decide whether regular formoterol and budesonide or beclomethasone have equivalent or different safety profiles from salmeterol and fluticasone.

Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events.

an increase in serious adverse events with both regular formoterol and regular salmeterol in chronic asthma has been demonstrated in comparison with placebo in previous Cochrane reviews. This increase was significant in trials that did not randomise participants to an inhaled corticosteroid, but less certain in the smaller numbers of participants in trials that included an inhaled corticosteroid in the randomised treatment regimen. we set out to compare the risks of mortality and non-fatal serious adverse events in trials which have randomised patients with chronic asthma to regular formoterol versus regular salmeterol, when each are used with an inhaled corticosteroid as part of the randomised treatment trials were identified using the Cochrane Airways Group Specialised Register of trials. Manufacturers' web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol were also checked. The date of the most recent search was July 2009. controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma were included if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid), and were of at least 12 weeks duration. two authors independently selected trials for inclusion in the review and extracted outcome data. Unpublished data on mortality and serious adverse events were sought from the sponsors and authors. eight studies met the eligibility criteria of the review recruiting 6,163 adults and adolescents. There were seven studies (involving 5,935 adults and adolescents) comparing formoterol and budesonide to salmeterol and fluticasone. All but one study administered the products as a combined inhaler, and most used formoterol 50 mcg and budesonide 400 mcg twice daily versus salmeterol 50 mcg and fluticasone 250 mcg twice daily. There were two deaths overall (one on each combination) and neither were thought to be related to asthma. There was no significant difference between treatment groups for non-fatal serious adverse events, either all-cause (Peto OR 1.14; 95% CI 0.82 to 1.59, I2 = 26%) or asthma-related (Peto OR 0.69; 95% CI 0.37 to 1.26, I2 = 33%). Over 23 weeks the rates for all-cause serious adverse events were 2.6% on formoterol and budesonide and 2.3% on salmeterol and fluticasone, and for asthma-related serious adverse events, 0.6% and 0.8% respectively. There was one study (228 adults) comparing formoterol and beclomethasone to salmeterol and fluticasone, but there were no deaths or hospital admissions. No studies were found in children. the seven identified studies in adults did not show any significant difference in safety between formoterol and budesonide in comparison with salmeterol and fluticasone. Asthma-related serious adverse events were rare, and there were no reported asthma-related deaths. There was a single small study comparing formoterol and beclomethasone to salmeterol and fluticasone in adults, but no serious adverse events occurred in this study. No studies were found in children. Overall there is insufficient evidence to decide whether regular formoterol and budesonide or beclomethasone have equivalent or different safety profiles from salmeterol and fluticasone.

Dispensing of fluticasone propionate/salmeterol combination in the summer and asthma-related outcomes in the fall

Asthma exacerbations occur year-round; however, peak asthma-related events occur in the fall and are frequently associated with viral respiratory infections. To compare the rates of asthma-related emergency department (ED) visits and hospitalizations in the fall (September, October, November) between users and nonusers of fluticasone propionate plus salmeterol in a single inhaler (FSC) in the preceding summer. This was a retrospective, observational study using health care claims from a large managed care database. Patients age 4 to 55 years with both a medical claim for asthma and a pharmacy claim for FSC were categorized into 3 age groups: children (4-11 years), adolescents (12-18 years), and adults (19-55 years). There were 201,973 observations of FSC dispensings and 184,143 observations without FSC. Across all age groups, summertime dispensings of FSC were associated with a significantly lower (P < .001) risk of an asthma-related ED visit (4-11 years: adjusted odds ratio [OR], 0.54, 95% CI, 0.49-0.60; 12-18 years: OR, 0.59, 95% CI, 0.54-0.64; 19-55 years: OR, 0.53, 95% CI, 0.51-0.55) or hospitalization (4-11 years: OR, 0.43, 95% CI, 0.35-0.54; 12-18 years: OR, 0.49, 95% CI, 0.40-0.60; 19-55 years: OR, 0.61, 95% CI, 0.57-0.65) in the subsequent fall. This protective effect persisted even for patients with fall dispensings of FSC. The risk of oral corticosteroid dispensing in the fall was also significantly reduced in all age groups. Summertime dispensings of FSC were associated with a decreased risk of serious asthma-related outcomes in the subsequent fall. Continuous use of FSC before seasonal viral exposure may decrease seasonally related exacerbations.

Safety of budesonide/formoterol maintenance and reliever therapy in asthma trials

The safety of long-acting beta(2)-agonists (LABAs) in asthma is debated. This study examined the safety of the inhaled corticosteroid (ICS)/LABA combination budesonide/formoterol dry powder inhaler used as maintenance and reliever therapy versus combination treatments based on guideline recommendations. Safety data from six double-blind, randomised clinical trials (RCTs) in asthma where budesonide/formoterol was used as maintenance and reliever therapy for at least 6 months were reviewed (N=14 346). All-cause mortality and asthma-related serious adverse events (SAEs) (co-primary endpoints), overall and cardiac SAEs, and discontinuations due to adverse events (DAEs) were assessed. Estimated Mantel-Haenszel (MH) relative risks (RR) with this regimen versus comparators were calculated. There was no increase in all-cause mortality with budesonide/formoterol maintenance and reliever therapy (four deaths [0.07%] versus nine [0.10%]; pooled MH RR 0.70, 95% confidence interval [CI] 0.21-2.30). Asthma-related SAEs were reduced with budesonide/formoterol maintenance and reliever therapy: 41 (0.73%) versus 121 (1.38%); pooled MH RR 0.59, 95% CI 0.42-0.85. All-cause and asthma-related DAEs were also reduced with budesonide/formoterol maintenance and reliever therapy: pooled MH RR 0.60 (95% CI 0.46-0.79) and 0.43 (0.28-0.68), respectively. Overall and cardiac-related SAEs were comparable between treatment groups: pooled MH RR 0.96 (95% CI 0.82-1.14) and 1.26 (0.72-2.22), respectively. Budesonide/formoterol dry powder inhaler maintenance and reliever therapy was well tolerated in RCTs versus fixed-dose alternatives and not associated with increased risk of death or cardiac-related SAEs and DAEs, and asthma-related SAEs and DAEs were significantly reduced. Given the limitations of RCTs, particularly exclusion of patients with co-morbidities, ongoing surveillance is appropriate.

Safety of Long-Acting β-Agonists: Are New Data Really Required?

Safety of Long-Acting β-Agonists: Are New Data Really Required?

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

Inhaled corticosteroid (ICS) therapy in combination with long-acting beta-adrenergic agonists represents the most important treatment for chronic airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). ICS therapy forms the basis for treatment of asthma of all severities, improving asthma control, lung function and preventing exacerbations of disease. Use of ICS has also been established in the treatment of COPD, particularly symptomatic patients, who experience useful gains in quality of life, likely from an improvement in symptoms such as breathlessness and in reduction in exacerbations, and an attenuation of the yearly rate of deterioration in lung function. The addition of long-acting beta-agonist (LABA) therapy with ICS increases the efficacy of ICS effects in moderate-to-severe asthma. Thus, a 800 mug daily dose of the ICS budesonide reduced severe exacerbation rates by 49% compared to a low dose of 200 mug daily, and addition of the LABA formoterol to budesonide (800 mug) led to a 63% reduction. In COPD, the effects of ICS are less prominent but there are beneficial effects on the decline in FEV(1) and the rate of exacerbations. A reduction in the rate of decline in FEV(1) of 16 ml/year with a 25% reduction in exacerbation rate has been reported with the salmeterol and fluticasone combination. A non-significant 17.5% reduction in all-cause mortality rate with ICS and LABA is reported. Chronic inflammation is a feature of both asthma and COPD, although there are site and characteristic differences. ICS targets this inflammation although this effect of ICS is less effective in patients with severe asthma and with COPD; however, addition of LABA may potentiate the anti-inflammatory effects of ICS. An important consideration is the presence of corticosteroid insensitivity in these patients. Currently available ICS have variably potent binding activities to specific glucocorticoid receptors, leading to inhibition of gene expression by either binding to DNA and inducing anti-inflammatory genes or by repressing the induction of pro-inflammatory mediators. Local side effects of ICS include oral candidiasis, hoarseness and dysphonia, while systemic side effects, such as easy bruising and reduction in growth velocity or bone mineral densitometry, are usually restricted to doses above maximally recommended doses. Use of LABA alone in patients with asthma increases the risk of asthma-related events including deaths, but this is less observed with the combination of ICS and LABA. Therefore, use of LABA alone is not recommended for asthma therapy. Future progress in ICS development will be characterised by the introduction of ICS with greater efficacy with a limited side-effect profile, and by longer-acting ICS that can be used in combination with once-daily LABAs. Other agents that could improve the efficacy of corticosteroids or reverse corticosteroid insensitivity may be added to ICS. ICS in combination with LABAs will continue to remain the main focus of treatment of airways diseases.

The safety of formoterol among patients with asthma using inhaled corticosteroids. Systematic review and meta‑analysis

It has been postulated that inhaled long acting beta-agonists (LABAs) when used as monotherapy in asthma may increase the incidence of asthma related deaths, intubations and hospitalizations, but concomitant use of inhaled corticosteroids (ICS) may modify this effect. To assess the safety of formoterol in patients with asthma using ICS. We conducted a systematic review and meta-analysis of parallel group, blinded, randomized controlled trials with at least 12 weeks of treatment examining the impact of twice a day formoterol on asthma-related and total morbidity and mortality in patients concurrently using ICS. Our main analysis considering impact of LABAs (salmeterol and formoterol) has already been published. In this report we present detailed information from studies investigating use of twice daily formoterol among patients receiving ICS. The search yielded 16 relevant studies included in this analysis. Among over 10,000 participants (5,996 taking formoterol with over 4,000 patient-years observation in formoterol groups) there were 2 asthma-related deaths (both in formoterol groups) and no asthma-related non-fatal intubations. The risk of asthma-related hospitalizations (odds ratio [OR] 0.59, 95% CI 0.37-0.93) and asthma-related serious adverse events (mostly hospitalizations) [OR 0.58, 95% CI 0.37-0.91] were significantly lower in patients on formoterol and ICS compared to patients on ICS alone. The OR for total mortality was 1.22, 95% CI 0.38-3.90, reflecting 7 deaths in formoterol groups and 3 deaths in control groups respectively. In patients with asthma using inhaled corticosteroids formoterol decreased the risk of asthma-related hospitalizations. There were too few asthma-related deaths and intubations to establish formoterol's relative impact on these outcomes.

Severe Exacerbations and Decline in Lung Function in Asthma

To evaluate the association between asthma exacerbations and the decline in lung function, as well as the potential effects of an inhaled corticosteroid, budesonide, on exacerbation-related decline in patients with asthma. To determine whether severe asthma exacerbations are associated with a persistent decline in lung function. The START (inhaled steroid treatment as regular therapy in early asthma) study was a 3-year, randomized, double-blind study of 7,165 patients (5-66 yr) with persistent asthma for less than 2 years, to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events (exacerbations requiring hospitalization or emergency treatment) and decline in lung function. There were 315 patients who experienced at least one severe asthma exacerbation, of which 305 were analyzable, 190 in the placebo group and 115 in the budesonide group. In the placebo group, the change in post-bronchodilator FEV(1) % predicted from baseline to the end of the study, in patients who did or did not experience a severe exacerbation was -6.44% and -2.43%, respectively (P < 0.001). A significant difference was seen in both children and in adults, but not in adolescents. In the budesonide group, the change in the post-bronchodilator FEV(1) % predicted in patients who did or did not experience a severe exacerbation was -2.48% and -1.72%, respectively (P = 0.57). The difference in magnitude of reduction afforded by budesonide, in patients who experienced at least one severe asthma-related event compared with those who did not, was statistically significant (P = 0.042). Severe asthma exacerbations are associated with a more rapid decline in lung function. Treatment with low doses of inhaled corticosteroid is associated with an attenuation of the decline.

The Safety of Long-Acting β-Agonists among Patients with Asthma Using Inhaled Corticosteroids

Inhaled long-acting beta-agonists (LABAs), when used as monotherapy in asthma, may increase asthma-related hospitalizations, life threatening events requiring intubation/mechanical ventilation, and asthma-related deaths, but concomitant use of inhaled corticosteroids (ICS) may modify this effect. To determine the safety of long-acting beta-agonists among patients with asthma using corticosteroids. We conducted a systematic review and metaanalysis of parallel-group, blinded, randomized, controlled trials with at least 12 weeks of treatment addressing the impact of LABA on asthma-related and total morbidity and mortality in patients concomitantly using ICS. We searched MEDLINE, EMBASE, ACPJC, and Cochrane (Central) databases, and contacted authors and sponsors. We used a random effects model to pool results from different studies as odds ratios (ORs) (95% confidence interval [CI]) (OR < 1.0 favors LABA). The search yielded 62 relevant studies included in this analysis. Among over 29,000 participants (15,710 taking LABA, with over 8,000 patient-years observed in the LABA groups), there were three asthma-related deaths and two asthma-related, nonfatal intubations (all in LABA groups; <or= one event per study). Differences in asthma-related hospitalizations (OR, 0.74; 95% CI, 0.53-1.03) and asthma-related serious adverse events (mostly hospitalizations; OR, 0.75; 95% CI, 0.54-1.03) failed to reach statistical significance. The OR for total mortality was 1.26 (95% CI, 0.58-2.74), reflecting 14 deaths in LABA groups and eight deaths in control groups, respectively. In patients with asthma using ICS, LABA did not increase the risk of asthma-related hospitalizations. There were very few asthma-related deaths and intubations, and events were too infrequent to establish LABA's relative effect on these outcomes.

Long-acting -agonists: a review of formoterol safety data from asthma clinical trials

The safety of long-acting beta(2)-agonist (LABA) treatment in asthma has been questioned following reported increased respiratory deaths when salmeterol was added to usual pharmacotherapy. The aim of this study was to examine whether asthma, cardiac or all-cause mortality and morbidity were increased with formoterol use. The analysis included all AstraZeneca randomised controlled parallel-group asthma trials of 3-12-months duration involving formoterol. Risks associated with formoterol use compared with non-LABA treatment, overall and in combination with inhaled corticosteroids (ICS), were assessed using an intention-to-treat analysis of the rates and rate ratios of deaths and serious adverse events (SAEs). The main objective of this study was to compare asthma-related mortality in patients using formoterol and those not using formoterol. There were eight asthma-related deaths (0.34 per 1,000 person-yrs) among 49,906 formoterol-randomised patients (92% using ICS), and two (0.22 per 1,000 person-yrs) among 18,098 patients (83% using ICS) not randomised to formoterol, which was nonsignificant. Asthma-related SAEs (>90% of which were hospitalisations) were significantly fewer among formoterol-randomised patients (0.75 versus 1.10%). There was no increase in asthma-related SAEs with increased daily doses of formoterol (9, 18 or 36 microg). There was no significant difference in cardiac mortality or noncardiac nonasthma-related mortality in formoterol-randomised compared to non-LABA-treated patients. All-cause mortality was similar. In the data set in which all subjects were prescribed ICS at baseline, there were seven asthma-related deaths (0.32 per 1,000 person-yrs) among 46,003 formoterol-randomised patients and one (0.14 per 1,000 person-yrs) among 13,905 patients not randomised to formoterol, which was also nonsignificant. There were few asthma-related or cardiac-related deaths among patients randomised to formoterol, and all differences were nonsignificant compared with non-long-acting beta(2)-agonist-randomised patients. However, despite data on >68,000 patients, the power was insufficient to conclude that there was no increased mortality with formoterol. Cardiac-related serious adverse events were not increased, and asthma-related serious adverse events were significantly reduced with formoterol.

Meta-analysis: Effects of Adding Salmeterol to Inhaled Corticosteroids on Serious Asthma-Related Events

Recent analyses have suggested an increased risk for serious asthma-related adverse events in patients receiving long-acting beta-agonists. To examine whether the incidences of severe asthma-related events (hospitalizations, intubations, deaths, and severe exacerbations) differ in persons receiving salmeterol plus inhaled corticosteroids compared with inhaled corticosteroids alone. The GlaxoSmithKline (Research Triangle Park, North Carolina) database, MEDLINE, EMBASE, CINAHL, and the Cochrane Database of Systemic Reviews (1982 to September 2007) were searched without language restriction. Randomized, controlled trials reported in any language that compared inhaled corticosteroids plus salmeterol (administered as fluticasone propionate/salmeterol by means of a single device or concomitant administration of inhaled corticosteroids and salmeterol) versus inhaled corticosteroids alone in participants with asthma. Three physicians independently reviewed and adjudicated blinded case narratives on serious adverse events that were reported in the GlaxoSmithKline trials. Data from 66 GlaxoSmithKline trials involving a total of 20 966 participants with persistent asthma were summarized quantitatively. The summary risk difference for asthma-related hospitalizations from these trials was 0.0002 (95% CI, -0.0019 to 0.00231; P = 0.84) for participants receiving inhaled corticosteroids plus salmeterol (n = 35 events) versus those receiving inhaled corticosteroids alone (n = 34 events). One asthma-related intubation and 1 asthma-related death occurred among participants receiving inhaled corticosteroids with salmeterol; no such events occurred among participants receiving inhaled corticosteroids alone. A subset of 24 trials showed a decreased risk for severe asthma-related exacerbations for inhaled corticosteroids plus salmeterol versus inhaled corticosteroids alone (risk difference, -0.025 [CI, -0.036 to -0.014]; P <0.001). The included trials involved selected patients who received careful follow-up. Only 26 trials were longer than 12 weeks. Few deaths and intubations limited the ability to measure risk for these outcomes. Salmeterol combined with inhaled corticosteroids decreases the risk for severe exacerbations, does not seem to alter the risk for asthma-related hospitalizations, and may not alter the risk for asthma-related deaths or intubations compared with inhaled corticosteroids alone.

Drug Safety and Salmeterol: The Controversy Continues

In this issue, Bateman and colleagues combined patient data from randomized efficacy trials to determine whether incidence of severe asthma-related events differs in persons receiving salmeterol pl...

Ecologic analysis of asthma-related events and dispensing of inhaled corticosteroid- and salmeterol-containing products

An association between salmeterol use and serious asthma episodes or asthma-related mortality has been noted in 2 clinical trials; however, a causal relationship has not been established. To date, observational studies have not replicated this finding. To examine the relationship between number of prescriptions dispensed of salmeterol-containing products and inhaled corticosteroid (ICS)-containing products and the rates of asthma-related hospitalizations and mortality in the United States. In this ecologic study, annual age-adjusted rates of asthma-related hospitalization and asthma-related mortality from US population-based sources were graphed alongside annual number of prescriptions dispensed of salmeterol- and ICS-containing products by year from 1991 to 2004. We computed the Spearman rank correlations between number of prescriptions dispensed and serious events (asthma-related hospitalization rate, number of hospitalizations, asthma-related mortality rate, and number of asthma deaths). During more than 14 years, while number of prescriptions dispensed of salmeterol-containing and ICS-containing products increased, age-adjusted asthma-related mortality rates declined and asthma-related hospitalization rates remained relatively stable. The number of asthma-related deaths has decreased steadily since the mid-1990s. This study provides population-level evidence that asthma-related death rates declined and asthma-related hospitalization rates remained relatively constant for more than 14 years during a period of improvements in asthma management per treatment guidelines, including increased use of maintenance medications, such as ICSs and salmeterol.

Confirmed β16 Arg/Arg Polymorphism in a Patient with Uncontrolled Asthma

To report a case of confirmed beta(16) Arg/Arg polymorphism (Arg/Arg) in a patient with uncontrolled asthma. A 49-year-old black female presented to the emergency department with acute shortness of breath with subsequent intubation. After extubation, she reported multiple hospitalizations for asthma with one prior intubation, adherence to asthma medications, and very frequent use of her short-acting beta(2)-agonist (SABA). Because of her asthma history, self-reported adherence, and race, she was tested for beta(2)-adrenoreceptor genotype, which revealed Arg/Arg. Based on these findings, beta(2)-agonists were discontinued and tiotropium (maintenance) and ipratropium (primary rescue) were initiated as part of her asthma regimen. Application of the Naranjo probability scale revealed probable causality between uncontrolled asthma in our patient and SABA use. The patient is followed in our outpatient pulmonary clinic and, at time of writing, had not been admitted to our hospital for asthma-related events. Approximately 15% of Americans with asthma are Arg/Arg, with an increased prevalence in black and Asian populations. It is hypothesized that changes in the degree of sensitivity or desensitization to the bronchodilator effect of beta(2)-agonists may occur in these individuals. Data exist, although they are conflicting, suggesting that inhaled beta(2)-agonists may worsen clinical outcomes. Trials have reported declines in peak expiratory flow rates plus increases in asthma symptoms and exacerbations when SABAs have been used regularly in patients with Arg/Arg. Studies evaluating long-acting beta(2)-agonists (LABAs) have inconsistent results. Preliminary data suggest that anticholinergics may serve as a beneficial primary rescue medication instead of beta(2)-agonists in patients with Arg/Arg. Clinicians should be aware of factors (eg, race and polymorphisms) that may predict unfavorable outcomes with regular SABA and possibly LABA use. Patients with poor asthma control despite adherence to asthma therapy may benefit from beta(2)-adrenoreceptor genotyping and, possibly, from anticholinergics.

Association of control and risk of severe asthma-related events in severe or difficult-to-treat asthma patients

Association of control and risk of severe asthma-related events in severe or difficult-to-treat asthma patients

A review of ibuprofen and acetaminophen use in febrile children and the occurrence of asthma-related symptoms

Background: Although many studies have investigated the safety and tolerability of ibuprofen or acetaminophen (paracetamol) use in children, few have specifically examined the association of ibuprofen or acetaminophen and the occurrence of asthma in pediatric populations. Objectives: The primary objective of this literature review was to ascertain whether ibuprofen use exacerbates the symptoms of asthma or asthma-related adverse events in febrile children, and how it compares with acetaminophen use. The secondary objective was to develop an algorithm that allows for the consideration of ibuprofen treatment in children by health care professionals. Methods: Twelve electronic databases (MEDLINE, EMBASE, Cochrane Database, DARE, British Nursing Index, CBIB, Derwent Drug File, International Pharmaceutical Abstracts, Pharm-Line, CINAHL, PASCAL, SCZZ-SciSearch) were searched from their year of inception to June 2007, to identify English-language articles pertaining to ibuprofen or acetaminophen use in the asthmatic pediatric population. The following search terms were used: asthma, child, pediatric, pediatrics, ibuprofen, Nurofen, Brufen, Motrin, Advil, propionic acid, paracetamol, and acetaminophen. Results: Of 472 articles retrieved, 3 were relevant for the development of the algorithm. Two were subanalyses of a major randomized controlled trial (RCT), the Boston University Fever Study. Therefore, some overlap should be noted. The third article was another RCT. Other studies and review articles identified were used for the discussion. Findings from the literature analysis indicated that the use of ibuprofen in the pediatric population does not exacerbate asthma morbidity. Two of the studies demonstrated that ibuprofen was associated with a lower risk for asthma morbidity in febrile children with or without asthma compared with acetaminophen. In one study, ibuprofen use was associated with a lower relative risk for hospitalization (0.63) and outpatient visits (0.56) for asthma compared with acetaminophen. In the second study, acetaminophen use was associated with the exacerbation of wheezing in febrile children. This observation was corroborated by the findings of other studies that revealed an increased risk for asthma, wheezing, and other atopic outcomes with acetaminophen use. Conclusions: The evidence reviewed in this article suggests a low risk for asthma-related morbidity associated with ibuprofen use in children and a possible protective and therapeutic effect compared with acetaminophen. The findings also suggest that acetaminophen use in children is associated with an increased risk for wheezing. The pediatric algorithm developed might serve as a guide for health care professionals in assessing suitability for ibuprofen use in children.

Effectiveness of omalizumab (Xolair ®) in the first patients treated in real-life practice in France

To describe omalizumab (Xolair) effectiveness in the first patients treated on compassionate grounds before its commercialisation in France. In a historic-prospective study, data were obtained by questionnaire from the physicians whose patients had received a nominative temporary use authorisation (ATU) for omalizumab from July 2003 to January 2006. Anonymised patient data regarding demographics, asthma-related treatments and events in the year previous to the start of omalizumab treatment as well as the details of omalizumab treatment itself were obtained at inclusion. Follow-up data at more than 3 months following inclusion were also obtained and regarded asthma-related treatment (including omalizumab), events and undesirable effects suspected to be linked to omalizumab treatment. Data were obtained for 147 of the 154 patients treated via ATU. 31.3% received inappropriate monthly doses of omalizumab. Of the 28 patients (19%) who discontinued for unsatisfactory therapeutic effect, 7 were treated for less than the 16 weeks recommended to evaluate efficacy and 9 who were treated for a longer period of time were underdosed. During the treatment period and compared to the previous year, patients with follow-up data at 5 months or more had experienced 62% fewer exacerbations requiring oral corticosteroids, 65% fewer emergency department visits and 29% fewer hospitalisations per year. The nature of adverse effects reported was similar to that reported in omalizumab clinical trials. Results strongly suggest that omalizumab in the first patients treated in real-life setting provided a similar benefit to that observed in clinical trials. Underdosing of patients may limit this therapeutic effect.