Regular Formoterol Research Articles

Regular formoterol plus inhaled corticosteroid vs. salmeterol plus inhaled corticosteroid for asthma

Dr. Steward and Dr. Sheth have no conflicts of interest to declare.

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

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

Inhaled steroids with and without regular formoterol for asthma: serious adverse events.

Inhaled steroids with and without regular formoterol for asthma: serious adverse events.

Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews

Background Two large surveillance studies in adults with asthma have found an increased risk of asthma-related mortality in those who took regular salmeterol as monotherapy in comparison to placebo or regular salbutamol. No similar sized surveillance studies have been carried out in children with asthma, and we remain uncertain about the comparative safety of regular combination therapy with either formoterol or salmeterol in children with asthma.

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

Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. Much debate has surrounded 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. This is an updated Cochrane Review. To assess the risk of fatal and non-fatal serious adverse events in people with chronic asthma given regular formoterol with inhaled corticosteroids versus the same dose of inhaled corticosteroids alone. Trials were identified using the Cochrane Airways Group Specialised Register of trials. Web sites of clinical trial registers were checked for unpublished trial data; Food and Drug Administration (FDA) submissions in relation to formoterol were also checked. The date of the most recent search was August 2012. Controlled clinical trials with a parallel design were included if they randomly allocated people of any age and severity of asthma to treatment with regular formoterol and inhaled corticosteroids for at least 12 weeks. We used standard methodological procedures expected by The Cochrane Collaboration. Unpublished data on mortality and serious adverse events were obtained from the sponsors. We assessed the quality of evidence using GRADE recommendations. Following the 2012 update, we have included 20 studies on 10,578 adults and adolescents and seven studies on 2788 children and adolescents. We found data on all-cause fatal and non-fatal serious adverse events for all studies, and we judged the overall risk of bias to be low.Six deaths occurred in participants taking regular formoterol with inhaled corticosteroids, and one in a participant administered regular inhaled corticosteroids alone. The difference was not statistically significant (Peto odds ratio (OR) 3.56, 95% confidence interval (CI) 0.79 to 16.03, low-quality evidence). All deaths were reported in adults, and one was believed to be asthma-related.Non-fatal serious adverse events of any cause were very similar for each treatment in adults (Peto OR 0.98, 95% CI 0.76 to 1.27, moderate-quality evidence), and weak evidence suggested an increase in events in children on regular formoterol (Peto OR 1.62, 95% CI 0.80 to 3.28, moderate-quality evidence).In contrast with all-cause serious adverse events, the addition of new trial data means that asthma-related serious adverse events associated with formoterol are now significantly fewer in adults taking regular formoterol with inhaled corticosteroids (Peto OR 0.49, 95% CI 0.28 to 0.88, moderate-quality evidence). Although a greater number of asthma-related events were reported in children receiving regular formoterol, this finding was not statistically significant (Peto OR 1.49, 95% CI 0.48 to 4.61, low-quality evidence). From the evidence in this review, it is not possible to reassure people with asthma that regular use of inhaled corticosteroids with formoterol carries no risk of increasing mortality in comparison with use of inhaled corticosteroids alone. On the other hand, we have found no conclusive evidence of serious harm, and only one asthma-related death was registered during more than 4200 patient-years of observation with formoterol.In adults, no significant difference in all-cause non-fatal serious adverse events was noted with regular formoterol with inhaled corticosteroids, but a significant reduction in asthma-related serious adverse events was observed in comparison with inhaled corticosteroids alone.In children the number of events was too small, and consequently the results too imprecise, to allow determination of whether the increased risk of all-cause non-fatal serious adverse events found in a previous meta-analysis on regular formoterol alone is abolished by the additional use of inhaled corticosteroids.We await the results of large ongoing surveillance studies mandated by the Food and Drug Administration (FDA) for more information. Clinical decisions and information provided to patients regarding regular use of formoterol have to take into account the balance between known symptomatic benefits of formoterol and the degree of uncertainty associated with its potential harmful effects.

Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events

Epidemiological evidence has suggested a link between beta2-agonists and increased asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta2-agonists are safe. This is an updated systematic review. To assess the risk of mortality and non-fatal serious adverse events in trials which randomised patients with chronic asthma to regular salmeterol and inhaled corticosteroids in comparison to the same dose of inhaled corticosteroids. We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data. Food and Drug Administration (FDA) submissions in relation to salmeterol were also checked. The date of the most recent search is August 2012. We included parallel design controlled clinical trials on patients of any age and severity of asthma if they randomised patients to treatment with regular salmeterol and inhaled corticosteroids (in separate or combined inhalers), and were of at least 12 weeks duration. We conducted the review according to standard procedures expected by the Cochrane Collaboration. We obtained unpublished data on mortality and serious adverse events from the sponsors, and from FDA submissions. We assessed the quality of evidence according to GRADE recommendations. We have included 35 studies (13,447 participants) in adults and adolescents, and 5 studies (1862 participants) in children in this review. We judged that the overall risk of bias was low, and we obtained data on serious adverse events from all studies. All except 542 adults (and none of the children) who were randomised to salmeterol were given fluticasone in the same (combination) inhaler.Seven deaths occurred in 6986 adults on regular salmeterol with inhaled corticosteroids (ICS), and seven deaths in 6461 adults on regular inhaled corticosteroids at the same dose. The difference was not statistically significant (Peto odds ratio (OR) 0.90; 95% confidence interval (CI) 0.31 to 2.60, moderate quality evidence). The risk of dying from any cause in adults on ICS was 10 per 10,000, and on salmeterol and ICS we would expect between 3 and 26 deaths per 10,000. No deaths were reported in 1862 children, and no deaths were reported to be asthma-related in adults or children.Non-fatal serious adverse events of any cause were reported in 167 adults on regular salmeterol with ICS, compared to 135 adults on regular ICS; again this was not a statistically significant increase (Peto OR 1.15; 95% CI 0.91 to 1.44, moderate quality evidence). The frequency of serious adverse events was 21 per 1000 in the adults treated with ICS and 24 per 1000 in those treated with salmeterol and ICS. The absolute difference in the risk of non-fatal serious adverse events was an increase of 3 per 1000, that was not statistically significant (risk difference (RD) 0.003; 95% CI -0.002 to 0.008).There were 6 of 930 children with serious adverse events on regular salmeterol with ICS, compared to 5 out of 932 on regular ICS: there was no significant difference between treatments (Peto OR 1.20; 95% CI 0.37 to 3.91, moderate quality evidence).Asthma-related serious adverse events were reported in 29 and 23 adults in each group respectively, a non-significant difference (Peto OR 1.12; 95% CI 0.65 to 1.94, moderate quality evidence), and only 1 asthma-related event was reported in children in each treatment group. We found no statistically significant differences in fatal or non-fatal serious adverse events in trials in which regular salmeterol was randomly allocated with ICS, in comparison to ICS alone at the same dose. Although 13,447 adults and 1862 children have now been included in trials, the frequency of adverse events is too low and the results are too imprecise to confidently rule out a relative increase in all cause mortality or non-fatal adverse events with salmeterol used in conjunction with ICS. However, the absolute difference between groups in the risk of serious adverse events was very small. We could not determine whether the increase in all cause non-fatal serious adverse events reported in the previous meta-analysis on regular salmeterol alone is abolished by the additional use of regular ICS. We await the results of large ongoing surveillance studies mandated by the FDA to provide more information. There were no asthma-related deaths and few asthma-related serious adverse events. Clinical decisions and information for patients regarding regular use of salmeterol have to take into account the balance between known symptomatic benefits of salmeterol and the degree of uncertainty and concern associated with its potential harmful effects.

The safety of regular long-acting beta2-agonists in children with asthma: an overview of Cochrane reviews

Two very large randomised trials (including over 50,000 participants) found an increase in asthma-related deaths in adults who were given regular salmeterol. Furthermore, individual patient data submitted to the FDA showed that the risks of serious adverse events while on regular formoterol or salmeterol were largest in the younger age-groups. This age-related trend was significant when regular formoterol or salmeterol were used with background inhaled corticosteroids (ICS), but was not found with combination inhalers. There are six separate Cochrane reviews looking at the safety of regular salmeterol or regular formoterol (with or without combination inhaled corticosteroids), and we have drawn data together into an overview of Cochrane reviews to summarise data on the serious adverse events in children from the randomised trials in all these reviews. We looked at children who suffered fatal and non-fatal (usually involving admission to hospital) serious adverse events of any cause, and also those related to asthma.

The Cochrane Library and safety of regular long‐acting beta2‐ agonists in children with asthma: an overview of reviews

AbstractBackground: Two large randomized trials of regular salmeterol monotherapy in adults with asthma found an increased risk of asthma‐related mortality for salmeterol versus placebo or regular salbutamol. There are no similar large trials in children, and the safety of monotherapy with salmeterol or other long‐acting beta2‐agonists in children with asthma is unclear. Current guidelines recommend that regular long‐acting beta2‐agonist therapy should be given only in combination with regular inhaled corticosteroids. However, the safety of combination therapy in children with asthma is also unclear.Objectives: We used the paediatric trial results from Cochrane systematic reviews to assess the safety of regular long‐acting beta2‐agonist therapy, either as monotherapy or as combination therapy with inhaled corticosteroids, in children with asthma.Methods: We searched the Cochrane Database of Systematic Reviews in May 2012 for Cochrane reviews relating to the safety of regular formoterol and salmeterol, and ran updated searches for trials for each of the Cochrane reviews. We used odds ratios (ORs) to summarize the direct randomized evidence on safety from trials comparing regular formoterol or regular salmeterol as monotherapy versus placebo and then as combination therapy with inhaled corticosteroids versus the same dose of inhaled corticosteroids. We indirectly compared the safety of monotherapy and combination therapy by testing for differences between the pooled ORs for monotherapy and for combination therapy. We used ORs to summarize the direct randomized evidence on safety from trials comparing regular formoterol with regular salmeterol. We also compared the safety of regular formoterol and regular salmeterol indirectly by calculating an OR for the pooled results of trials assessing formoterol and the pooled results of trials assessing salmeterol, and then combined the direct and indirect evidence by calculating an overall OR for this comparison.Results: We identified four Cochrane reviews examining the safety of regular formoterol or salmeterol as either monotherapy or combination therapy. The reviews included 19 trials in children and we found two additional studies on salmeterol combination therapy, for a total of 21 trials in 7318 children. We identified two Cochrane reviews comparing the safety of formoterol with salmeterol, which included a single trial in 156 children. We found a statistically significant increase in the odds of suffering a nonfatal serious adverse event in children on formoterol monotherapy [OR = 2.48; 95% confidence interval (CI) = 1.27–4.83, I2 = 0%, five trials, N = 1335] and smaller nonsignificant increases in odds for salmeterol monotherapy (OR = 1.30; 95% CI = 0.82–2.05, I2 = 17%, five trials, N = 1333), formoterol combination therapy (OR = 1.60; 95% CI = 0.80–3.28, I2 = 32%, seven trials, N = 2788) and salmeterol combination therapy (OR = 1.20; 95% CI = 0.37–2.91, I2 = 0%, five trials, N = 1862). There was no significant difference between the pooled ORs of a serious adverse event on monotherapy (OR = 1.60; 95% CI = 1.10–2.33, 10 trials, N = 2668) and combination therapy (OR = 1.50; 95% CI = 0.82–2.75, 12 trials, N = 4650). However, there was an absolute increase of 21 children (95% CI = 4–45) suffering a severe adverse event of any cause for every thousand children treated over six months on monotherapy, compared with an absolute increase of three (95% CI = 1 fewer to 12 more) per 1000 children over three months on combination therapy. The evidence comparing the safety of regular salmeterol to regular formoterol was limited, and even when direct and indirect evidence were combined, the CI around the effect on serious adverse events was too wide to tell whether there was a difference in the comparative safety of formoterol and salmeterol (OR = 1.26; 95% CI = 0.37–4.32). Only one child died across all the trials, so the impact on mortality could not be assessed.Authors' conclusions: Although regular combination therapy is likely to be safer than monotherapy in children with asthma, the safety of regular combination therapy with formoterol or salmeterol in children remains uncertain, particularly in terms of mortality. The relative safety of formoterol and salmeterol is also unclear. There are currently large ongoing surveillance studies that may clarify the risks of combination therapy in children and adolescents with asthma. Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. The Cochrane Collaboration

Safety of regular formoterol or salmeterol in children with asthma: an overview of Cochrane reviews

Safety of regular formoterol or salmeterol in children with asthma: an overview of Cochrane reviews

Regular treatment with formoterol for chronic asthma: serious adverse events.

Epidemiological evidence has suggested a link between beta(2)-agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta(2)-agonists are safe. The 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 versus placebo or regular short-acting beta(2)-agonists. We identified trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol. The date of the most recent search was January 2012. We included controlled, parallel design clinical trials on patients of any age and severity of asthma if they randomised patients to treatment with regular formoterol and were of at least 12 weeks' duration. Concomitant use of inhaled corticosteroids was allowed, as long as this was not part of the randomised treatment regimen. Two authors independently selected trials for inclusion in the review. One author extracted outcome data and the second author checked them. We sought unpublished data on mortality and serious adverse events. The review includes 22 studies (8032 participants) comparing regular formoterol to placebo and salbutamol. Non-fatal serious adverse event data could be obtained for all participants from published studies comparing formoterol and placebo but only 80% of those comparing formoterol with salbutamol or terbutaline.Three deaths occurred on regular formoterol and none on placebo; this difference was not statistically significant. It was not possible to assess disease-specific mortality in view of the small number of deaths. Non-fatal serious adverse events were significantly increased when regular formoterol was compared with placebo (Peto odds ratio (OR) 1.57; 95% CI 1.06 to 2.31). One extra serious adverse event occurred over 16 weeks for every 149 people treated with regular formoterol (95% CI 66 to 1407 people). The increase was larger in children than in adults, but the impact of age was not statistically significant. Data submitted to the FDA indicate that the increase in asthma-related serious adverse events remained significant in patients taking regular formoterol who were also on inhaled corticosteroids.No significant increase in fatal or non-fatal serious adverse events was found when regular formoterol was compared with regular salbutamol or terbutaline. In comparison with placebo, we have found an increased risk of serious adverse events with regular formoterol, and this does not appear to be abolished in patients taking inhaled corticosteroids. The effect on serious adverse events of regular formoterol in children was greater than the effect in adults, but the difference between age groups was not significant.Data on all-cause serious adverse events should be more fully reported in journal articles, and not combined with all severities of adverse events or limited to those events that are thought by the investigator to be drug-related.

Regular treatment with formoterol versus regular treatment with salmeterol 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 previous Cochrane reviews. 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. We identified trials using the Cochrane Airways Group Specialised Register of trials. We checked manufacturers' websites of clinical trial registers for unpublished trial data and also checked Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was January 2012. We included controlled, parallel-design clinical trials on patients of any age and with any severity of asthma if they randomised patients to treatment with regular formoterol versus regular salmeterol (without randomised inhaled corticosteroids), and were of at least 12 weeks' duration. Two authors independently selected trials for inclusion in the review and extracted outcome data. We sought unpublished data on mortality and serious adverse events from the sponsors and authors. The review included four studies (involving 1116 adults and 156 children). All studies were open label and recruited patients who were already taking inhaled corticosteroids for their asthma, and all studies contributed data on serious adverse events. All studies compared formoterol 12 μg versus salmeterol 50 μg twice daily. The adult studies were all comparing Foradil Aerolizer with Serevent Diskus, and the children's study compared Oxis Turbohaler to Serevent Accuhaler. There was only one death in an adult (which was unrelated to asthma) and none in children, and there were no significant differences in non-fatal serious adverse events comparing formoterol to salmeterol in adults (Peto odds ratio (OR) 0.77; 95% confidence interval (CI) 0.46 to 1.28), or children (Peto OR 0.95; 95% CI 0.06 to 15.33). Over a six-month period, in studies involving adults that contributed to this analysis, the percentages with serious adverse events were 5.1% for formoterol and 6.4% for salmeterol; and over a three-month period the percentages of children with serious adverse events were 1.3% for formoterol and 1.3% for salmeterol. We identified four studies comparing regular formoterol to regular salmeterol (without randomised inhaled corticosteroids, but all participants were on regular background inhaled corticosteroids). The events were infrequent and consequently too few patients have been studied to allow any firm conclusions to be drawn about the relative safety of formoterol and salmeterol. Asthma-related serious adverse events were rare and there were no reported asthma-related deaths.

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.

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.

Formoterol mono- and combination therapy with tiotropium in patients with COPD: A 6-month study

Although guidelines recommend combining long-acting bronchodilators in COPD, data are limited. We examined the clinical efficacy and safety of formoterol, tiotropium and the combination in patients with COPD. Eight hundred and forty-seven patients with COPD (mean FEV(1) 52% predicted; FEV(1)/FVC 53%) were randomized to receive one of the following four treatments for 24 weeks: formoterol 10 microg b.i.d. plus tiotropium 18 microg o.d.; formoterol 10 microg b.i.d.; tiotropium 18 microg o.d., or placebo. The study was partially blinded (formoterol and placebo). For the primary endpoint, FEV(1) 2h post-dose after 24 weeks, there were small differences in favour of the combination therapy versus formoterol (0.07 L, p=0.044) or tiotropium (0.06 L, p=0.066). All three treatments were superior to placebo (p<0.001). The combination was statistically superior to monotherapy for: the primary endpoint (p=0.044 vs. formoterol); FEV(1) 5 min after the first dose (p<0.001) and at 12 weeks (p<0.05 vs. tiotropium); and peak expiratory flow averaged over the first 6 weeks (p<0.001 vs. both). The three active treatments were significantly more effective than placebo for secondary endpoints: COPD-related 'bad days', symptoms, use of rescue medication and peak expiratory flow, and aspects of health-related quality of life. The overall incidence of adverse events was similar with all active treatments, although COPD-related adverse events were more common with tiotropium. Combined bronchodilator therapy may be a valuable treatment option for patients with COPD.

Rapid onset of tolerance to beta-agonist bronchodilation

Regular use of beta-agonists leads to tolerance to their bronchodilator effects. This is easily demonstrated if dilation is tested following methacholine challenge. It is not known how quickly tolerance develops or how long it lasts after stopping beta-agonist therapy. Ten subjects with stable asthma were studied. Following 2 weeks without beta-agonists, methacholine was inhaled to induce a 20% reduction in FEV1. The response to inhaled salbutamol (100, 100, 200 microg at 5-min intervals) was then measured. This procedure was repeated 24 h after one dose and 24 h after 3, 7 and 14 days of inhaled formoterol 12 microg twice daily, and 3 and 5 days after formoterol was discontinued. Unscheduled use of beta-agonists was not permitted. Bronchodilator tolerance, assessed by a reduction of the area under the salbutamol dose-response curve, occurred after 1 dose of formoterol (28% reduction, 95% CI 12, 45%), increased up to 1 week and plateaued between 1 and 2 weeks (58% reduction, 95% CI 38, 78%). Three days after stopping formoterol, the response to salbutamol was similar to baseline (12% reduction, 95% CI -9, 33%). The first dose of formoterol provided significant bronchoprotection to methacholine (1.6 doubling doses, P=0.007). This diminished with regular treatment and by 2 weeks the PD20 methacholine was not significantly different to baseline. Bronchodilator tolerance occurs after a single dose and reaches a maximum after 1 week of regular formoterol. Sensitivity recovers 3 days after stopping treatment.

Cross-tolerance to albuterol occurs independently of β 2-adrenoceptor genotype-16 in asthmatic patients receiving regular formoterol or salmeterol

Rationale We evaluated the Arg-16 and Gly-16 genotypes for the acute albuterol response following methacholine challenge, after the first and last doses of combination inhalers containing formoterol (FM) and salmeterol (SM). Methods Parallel groups of matched 10 homozygous Arg-16 and 10 homozygous Gly-16 asthmatics completed a randomized, double-blind, double-dummy, cross-over study. During a 1-week washout period prior to each randomized treatment, patients continued on their usual inhaled corticosteroid therapy. Patients received 2 weeks of either budesonide (BUD) 200 μg + FM 6 μg, 2 puffs bid, or fluticasone propionate (FP) 250 μg + SM 50 μg, 1 puff bid. After washouts and randomized treatments, 1 hour post first and last dose of combination inhalers, a methacholine challenge was performed followed by albuterol 200 μg, with recovery over 30 minutes (the primary outcome). Results Washout values for FEV 1, methacholine PC 20 and albuterol recovery were all similar for both treatments and genotypes. Pre-challenge FEV 1 values for both genotypes were not significantly different comparing first vs. last doses of each treatment. Albuterol recovery as area under the 30-minute time-response curve (%.min) was significantly delayed ( p<0.05) equally in both genotypes and treatments, comparing the first doses of BUD+FM (Arg-16: 386, Gly-16: 352) or FP+SM (Arg-16: 363, Gly-16: 289), vs. the last doses respectively of BUD+FM (Arg-16: 591, Gly-16: 491) or FP+SM (Arg-16: 529, Gly-16: 466). There were no differences in albuterol recovery comparing either genotypes or treatments. Conclusion Acute albuterol recovery in methacholine constricted airways was significantly delayed to a similar degree in both genotypes, due to cross-tolerance induced by FM or SM.

Bronchodilator Response to Albuterol After Regular Formoterol and Effects of Acute Corticosteroid Administration

There is controversy about the development of bronchodilator subsensitivity after regular administration of long-acting beta(2)-agonists. The purpose of the study was to evaluate whether regular treatment with formoterol affects the bronchodilator response to repeated puffs of albuterol, and also to assess the effects of acute administration of a bolus dose of IV or inhaled corticosteroid. Twelve patients (mean [SD] age, 43 [15] years; FEV(1), 57 [17] % predicted) with stable, moderate to severe persistent asthma who were all taking inhaled corticosteroids were evaluated in a randomized, placebo-controlled, double-blind, double-dummy, crossover study. Patients received treatments each for 2 weeks followed by a bolus (IV/inhaled) of corticosteroid or placebo: (1) placebo inhaler bid + bolus placebo; (2) formoterol Turbuhaler 24 microg metered dosage bid (delivered dosage 18 microg bid) + placebo; (3) formoterol 24 microg bid + bolus IV hydrocortisone, 200 mg; or (4) formoterol 24 microg bid + bolus inhaled budesonide, 1,600 microg. Bronchodilator response to repeated puffs of albuterol (200 to 1,600 microg) for > 80 min was measured at 2 h after bolus administration of placebo or corticosteroid. The study was powered at the 80% level to detect a 20% difference in area under curve between 20 and 80 min (AUC) for FEV(1) response to albuterol as change from baseline (primary end point). There was significant subsensitivity (p = 0.01) of the mean albuterol FEV(1) response (as AUC, L x s) after formoterol alone (737) as compared to placebo (1,453) along with partial reversal by steroid administration: formoterol + hydrocortisone (1, 050), and formoterol + budesonide (942). There was a similar pattern of subsensitivity (p = 0.03) for the mean albuterol forced expiratory flow between 25% and 75% of vital capacity response (as AUC, L): placebo (2,149), formoterol alone (1,002), formoterol + hydrocortisone (1,402), and formoterol + budesonide (1,271). Regular treatment with formoterol produced significant bronchodilator subsensitivity to repeated puffs of albuterol, which was partially reversed by a bolus dose of systemic or inhaled corticosteroid.

Sustained bronchoprotection, bronchodilatation, and symptom control during regular formoterol use in asthma of moderate or greater severity

Background: Recent studies have raised concern that regular inhalation of β 2 -agonists may cause a worsening of asthma control compared with on-demand dosing regimens. Objective: The objective of this study was to compare the effect of twice daily formoterol (Foradil), 4 times daily albuterol, and on-demand albuterol on bronchial hyperresponsiveness (BHR), lung function measurements, symptoms, and other indicators of disease control over 6 months inpatients with asthma of moderate or greater severity receiving concomitant inhaled corticosteroids. We also looked for occurrence of rebound BHR on discontinuation of treatment. Methods: This was a multicenter, parallel-group, double-blind, clinical trial. Methacholine PC 20 was the primary outcome variable. Other outcome variables included symptom scores, use of rescue medication, morning peak expiratory flow (PEF), serial FEV 1 measurements, and asthma exacerbations. Results: Of the 271 randomized patients, 217 completed the study. Formoterol was significantly superior to on-demand albuterol with regard to methacholine PC 20 , FEV 1 , PEF, symptom scores, and use of rescue medication at each measured time point/interval. Regular albuterol was superior to on-demand albuterol with regard to PC 20 and FEV 1 , but not PEF or various clinical scores. After a small drop in the magnitude of bronchoprotection and bronchodilatation occurring shortly after randomization, there was no evidence of progressive tolerance to either regular treatment for any of the measured variables or of rebound increase in BHR 2 days after the end of treatment. The formoterol group had the lowest number of exacerbation days, as defined by high intake of rescue bronchodilator and/or symptom scores, whereas the number of exacerbations requiring increased corticosteroid coverage was similar in the 3 groups. Conclusion: In patients with asthma of moderate or greater severity receiving inhaled corticosteroids, formoterol taken twice daily resulted in superior bronchoprotection, bronchodilatation, and clinical control compared with on-demand albuterol over 6 months. Four times daily albuterol was superior to on-demand albuterol for only some of the end points. Progressive tolerance and a rebound increase in BHR on discontinuation of β-agonists were not found (J Allergy Clin Immunol 1999;103:427-35.)

A Bolus of Inhaled Budesonide Rapidly Reverses Airway Subsensitivity and β2-Adrenoceptor Down-regulation After Regular Inhaled Formoterol

Subsensitivity of airway beta2-adrenoceptors develops readily in asthmatics receiving regular long-acting beta2-agonists. This subsensitivity may be rapidly reversed by using systemic corticosteroids. The purpose of the present study was to investigate whether the same acute facilitatory effects occur when using a bolus dose of inhaled corticosteroid. Ten subjects with stable mild-to-moderate asthma, with a mean age of 27 years, mean (+/- SD) FEV1 of 2.95 L (0.94 L), 81% (15%) of predicted, all receiving inhaled corticosteroids, reactive to adenosine monophosphate (AMP) with a provocative concentration producing a 20% fall in FEV1 (PC20) < 200 mg/mL, were recruited into a randomized double-blind crossover study. The subjects received two separate 1-week treatment periods with formoterol dry powder, 24 microg bid, with an initial 1-week run-in and a 1-week washout period between the treatments. A single dose of placebo or budesonide turbuhaler, 1,600 microg, was taken in conjunction with the last dose of both treatment periods. AMP challenge was performed 2 h after the first and last dose of formoterol. Blood for lymphocyte beta2-adrenoceptor density (Bmax) was also measured before and after treatment with formoterol. There was no significant difference in the geometric mean PC20 after the first dose of formoterol comparing the two treatment periods: 362 mg/mL vs 391 mg/mL. The PC20 after the last dose of formoterol was significantly higher (p < 0.05) in conjunction with budesonide than with placebo: 427 mg/mL vs 99 mg/mL, amounting to a 4.3-fold difference (95% confidence interval [CI], 1.1 to 16.6). For comparison within each treatment period, there was significant subsensitivity (p < 0.05) between the first and last dose of formoterol when the latter was given with placebo: 391 mg/mL vs 99 mg/mL, a 3.9-fold fall (95% CI, 1.0 to 15.2), but not when the latter was given with budesonide: 362 mg/mL vs 427 mg/mL, a 1.2-fold rise (95% CI, 0.5 to 2.8). Lymphocyte 02-adrenoceptor density (geometric mean Bmax: fmol/10(6) cells) also showed significant down-regulation (p < 0.05) by formoterol given with placebo: preformoterol 2.53 vs postformoterol 1.91, but not by formoterol given with budesonide: preformoterol 2.43 vs postformoterol 2.67. The Bmax was significantly higher (p < 0.05) with formoterol + budesonide as compared to formoterol + placebo, amounting to a 1.40-fold difference (95% CI, 1.09 to 1.80). We have shown that a bolus dose of inhaled budesonide rapidly reverses subsensitivity to AMP bronchoprotection and associated beta2-adrenoceptor down-regulation in asthmatics taking regular formoterol. Further studies are indicated to assess whether high-dose inhaled corticosteroids should be administered as soon as possible along with beta2-agonists during an acute episode of bronchoconstriction.