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

Abstract

No significant differences have been found in fatal or non-fatal serious adverse events in trials in which regular salmeterol has been randomly allocated with inhaled corticosteroids, in comparison to inhaled corticosteroids at the same dose. Although 10,873 adults and 1,173 children have been included in trials, the number of patients suffering adverse events is too small, and the results are too imprecise to confidently rule out a relative increase in all-cause mortality or non-fatal adverse events. It is therefore not possible to 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 inhaled corticosteroids. The absolute difference between groups in the risk of serious adverse events was small. 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.

Long-Acting Beta Agonists Enhance Allergic Airway Disease

“…Moreover, as the mechanism has an immune basis involving the aberrant activation of STAT6, our findings further explain the ability of glucocorticosteroids when added to salmeterol to mask in part this untoward effect. Interestingly, addition of glucocorticosteroids to formoterol does not necessarily mask the pro-asthmatic potential, and thus morbidity, of this LABA [15], nor is it clear that addition of glucocorticosteroids entirely block the pro-asthmatic potential of salmeterol with long-term use [14]. Our data further support these observations because although glucocorticosteroids have a clear anti-asthmatic effect (Fig 1C), LABAs activate STAT6 even in the presence of glucocorticosteroids and are alone sufficient to induce asthma-like airway obstruction in the complete absence of allergen provocation (Fig 1D and 1H; S3 Fig). A limitation of these studies is that they were conducted necessarily in vitro and in vivo using an experimental model of asthma.…”

Long-Acting Beta Agonists Enhance Allergic Airway Disease

“…Moreover, as the mechanism has an immune basis involving the aberrant activation of STAT6, our findings further explain the ability of glucocorticosteroids when added to salmeterol to mask in part this untoward effect. Interestingly, addition of glucocorticosteroids to formoterol does not necessarily mask the pro-asthmatic potential, and thus morbidity, of this LABA [15], nor is it clear that addition of glucocorticosteroids entirely block the pro-asthmatic potential of salmeterol with long-term use [14]. Our data further support these observations because although glucocorticosteroids have a clear anti-asthmatic effect (Fig 1C), LABAs activate STAT6 even in the presence of glucocorticosteroids and are alone sufficient to induce asthma-like airway obstruction in the complete absence of allergen provocation (Fig 1D and 1H; S3 Fig). A limitation of these studies is that they were conducted necessarily in vitro and in vivo using an experimental model of asthma.…”

Safety of formoterol in asthma clinical trials: an update

“…However, the data reported in the present paper, together with the many other meta-analyses and systematic reviews of the existing literature that have been undertaken [5][6][7][8][9][10][11][12][13], are consistent with the likelihood that the problem associated with use of LABAs in asthma is not an intrinsic safety issue related to the LABA itself, but to the overall management of the condition and the lack of appropriate treatment with ICS [23,28,32]. A number of Cochrane reviews [33][34][35][36][37] have addressed the safety of LABA/ICS combinations compared to use of ICS alone, and concluded that while combination therapy in general is favourable compared to ICS-alone treatment in adults, the results are less clear in children for whom limited data are yet available.…”

The impact of Cochrane Reviews: a mixed-methods evaluation of outputs from Cochrane Review Groups supported by the National Institute for Health Research

“…55 l Reviews on long-acting beta-antagonists in asthma [56][57][58] may have led to safer prescribing of these drugs for people with asthma (www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationfor PatientsandProviders/ucm200776.htm). l A review on colloids versus crystalloids for fluid resuscitation 59,60 may have influenced calls to stop starch use within the NHS, a decision that has the potential to save both lives and money.…”

Long-Acting Beta Agonists Enhance Allergic Airway Disease

“…Moreover, as the mechanism has an immune basis involving the aberrant activation of STAT6, our findings further explain the ability of glucocorticosteroids when added to salmeterol to mask in part this untoward effect. Interestingly, addition of glucocorticosteroids to formoterol does not necessarily mask the pro-asthmatic potential, and thus morbidity, of this LABA [15], nor is it clear that addition of glucocorticosteroids entirely block the pro-asthmatic potential of salmeterol with long-term use [14]. Our data further support these observations because although glucocorticosteroids have a clear anti-asthmatic effect (Fig 1C), LABAs activate STAT6 even in the presence of glucocorticosteroids and are alone sufficient to induce asthma-like airway obstruction in the complete absence of allergen provocation (Fig 1D and 1H; S3 Fig). A limitation of these studies is that they were conducted necessarily in vitro and in vivo using an experimental model of asthma.…”

Safety of formoterol in asthma clinical trials: an update

“…However, the data reported in the present paper, together with the many other meta-analyses and systematic reviews of the existing literature that have been undertaken [5][6][7][8][9][10][11][12][13], are consistent with the likelihood that the problem associated with use of LABAs in asthma is not an intrinsic safety issue related to the LABA itself, but to the overall management of the condition and the lack of appropriate treatment with ICS [23,28,32]. A number of Cochrane reviews [33][34][35][36][37] have addressed the safety of LABA/ICS combinations compared to use of ICS alone, and concluded that while combination therapy in general is favourable compared to ICS-alone treatment in adults, the results are less clear in children for whom limited data are yet available.…”

The impact of Cochrane Reviews: a mixed-methods evaluation of outputs from Cochrane Review Groups supported by the National Institute for Health Research

“…55 l Reviews on long-acting beta-antagonists in asthma [56][57][58] may have led to safer prescribing of these drugs for people with asthma (www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationfor PatientsandProviders/ucm200776.htm). l A review on colloids versus crystalloids for fluid resuscitation 59,60 may have influenced calls to stop starch use within the NHS, a decision that has the potential to save both lives and money.…”

Long-Acting Beta Agonists Enhance Allergic Airway Disease

“…Moreover, as the mechanism has an immune basis involving the aberrant activation of STAT6, our findings further explain the ability of glucocorticosteroids when added to salmeterol to mask in part this untoward effect. Interestingly, addition of glucocorticosteroids to formoterol does not necessarily mask the pro-asthmatic potential, and thus morbidity, of this LABA [15], nor is it clear that addition of glucocorticosteroids entirely block the pro-asthmatic potential of salmeterol with long-term use [14]. Our data further support these observations because although glucocorticosteroids have a clear anti-asthmatic effect (Fig 1C), LABAs activate STAT6 even in the presence of glucocorticosteroids and are alone sufficient to induce asthma-like airway obstruction in the complete absence of allergen provocation (Fig 1D and 1H; S3 Fig). A limitation of these studies is that they were conducted necessarily in vitro and in vivo using an experimental model of asthma.…”

Safety of formoterol in asthma clinical trials: an update

“…However, the data reported in the present paper, together with the many other meta-analyses and systematic reviews of the existing literature that have been undertaken [5][6][7][8][9][10][11][12][13], are consistent with the likelihood that the problem associated with use of LABAs in asthma is not an intrinsic safety issue related to the LABA itself, but to the overall management of the condition and the lack of appropriate treatment with ICS [23,28,32]. A number of Cochrane reviews [33][34][35][36][37] have addressed the safety of LABA/ICS combinations compared to use of ICS alone, and concluded that while combination therapy in general is favourable compared to ICS-alone treatment in adults, the results are less clear in children for whom limited data are yet available.…”

The impact of Cochrane Reviews: a mixed-methods evaluation of outputs from Cochrane Review Groups supported by the National Institute for Health Research

“…55 l Reviews on long-acting beta-antagonists in asthma [56][57][58] may have led to safer prescribing of these drugs for people with asthma (www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationfor PatientsandProviders/ucm200776.htm). l A review on colloids versus crystalloids for fluid resuscitation 59,60 may have influenced calls to stop starch use within the NHS, a decision that has the potential to save both lives and money.…”