Regular treatment with formoterol for chronic asthma: serious adverse events

Abstract

Background 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. Objectives 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. Search methods 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 We checked websites of clinical trial registers for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol.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. Selection criteria 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. Data collection and analysis 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 We sought unpublished data on mortality and serious adverse events. Main results 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 Regular treatment with formoterol for chronic asthma: serious adverse events (Review)

Rosiglitazone reverses salbutamol‐induced β2‐adrenoceptor tolerance in airway smooth muscle

“…late β 2 ‐adrenoceptor hyporesponsiveness and hyperreactivity mediated by muscarinic receptors) are a common feature of homologous β 2 ‐adrenoceptor desensitization (Nino et al ., 2009). Finally, the guinea‐pig model of salbutamol‐induced β 2 ‐adrenoceptor tolerance described in the present study closely resembles the clinical setting as the regular use of β 2 ‐adrenoceptor agonist bronchodilators has been associated with bronchial hyperresponsiveness and loss of bronchoprotection in asthma patients, a proasthmatic phenotype that increases the risk of asthma exacerbation during long‐term use of these drugs (Spitzer et al ., 1992; Cates et al ., 2008).…”

Rosiglitazone reverses salbutamol‐induced β2‐adrenoceptor tolerance in airway smooth muscle

“…late β 2 ‐adrenoceptor hyporesponsiveness and hyperreactivity mediated by muscarinic receptors) are a common feature of homologous β 2 ‐adrenoceptor desensitization (Nino et al ., 2009). Finally, the guinea‐pig model of salbutamol‐induced β 2 ‐adrenoceptor tolerance described in the present study closely resembles the clinical setting as the regular use of β 2 ‐adrenoceptor agonist bronchodilators has been associated with bronchial hyperresponsiveness and loss of bronchoprotection in asthma patients, a proasthmatic phenotype that increases the risk of asthma exacerbation during long‐term use of these drugs (Spitzer et al ., 1992; Cates et al ., 2008).…”

Cardiovascular mortality and morbidity in chronic obstructive pulmonary disease: the impact of bronchodilator treatment

“…Meta‐analyses of LABA use in asthma found an increase in non‐fatal serious events, 48,49 but not for cardiovascular mortality or non‐fatal cardiovascular events. In contrast, LABA use in COPD has been associated with an increased respiratory mortality, 50 although the accuracy of the cause of death was uncertain and the authors comment that confounding by cardiovascular deaths was possible.…”

Primary Care of the Patient with Asthma

“…They are not recommended as monotherapy in asthma, however, because of a slightly increased risk for serious adverse events, including death or severe asthma exacerbations. 53,54 Combination inhaler products that use a moderatedose ICS in addition to a LABA, such as budesonide/formoterol 80/4.5 or fluticasone 250 mg/salmeterol 50 mg, are safer and more effective than monotherapy with a LABA 55 and should be prescribed for those with symptoms that persist despite at least moderate-dose ICS. 35 …”

Rosiglitazone reverses salbutamol‐induced β2‐adrenoceptor tolerance in airway smooth muscle

“…late β 2 ‐adrenoceptor hyporesponsiveness and hyperreactivity mediated by muscarinic receptors) are a common feature of homologous β 2 ‐adrenoceptor desensitization (Nino et al ., 2009). Finally, the guinea‐pig model of salbutamol‐induced β 2 ‐adrenoceptor tolerance described in the present study closely resembles the clinical setting as the regular use of β 2 ‐adrenoceptor agonist bronchodilators has been associated with bronchial hyperresponsiveness and loss of bronchoprotection in asthma patients, a proasthmatic phenotype that increases the risk of asthma exacerbation during long‐term use of these drugs (Spitzer et al ., 1992; Cates et al ., 2008).…”

Cardiovascular mortality and morbidity in chronic obstructive pulmonary disease: the impact of bronchodilator treatment

“…Meta‐analyses of LABA use in asthma found an increase in non‐fatal serious events, 48,49 but not for cardiovascular mortality or non‐fatal cardiovascular events. In contrast, LABA use in COPD has been associated with an increased respiratory mortality, 50 although the accuracy of the cause of death was uncertain and the authors comment that confounding by cardiovascular deaths was possible.…”

Primary Care of the Patient with Asthma

“…They are not recommended as monotherapy in asthma, however, because of a slightly increased risk for serious adverse events, including death or severe asthma exacerbations. 53,54 Combination inhaler products that use a moderatedose ICS in addition to a LABA, such as budesonide/formoterol 80/4.5 or fluticasone 250 mg/salmeterol 50 mg, are safer and more effective than monotherapy with a LABA 55 and should be prescribed for those with symptoms that persist despite at least moderate-dose ICS. 35 …”

Rosiglitazone reverses salbutamol‐induced β2‐adrenoceptor tolerance in airway smooth muscle

“…late β 2 ‐adrenoceptor hyporesponsiveness and hyperreactivity mediated by muscarinic receptors) are a common feature of homologous β 2 ‐adrenoceptor desensitization (Nino et al ., 2009). Finally, the guinea‐pig model of salbutamol‐induced β 2 ‐adrenoceptor tolerance described in the present study closely resembles the clinical setting as the regular use of β 2 ‐adrenoceptor agonist bronchodilators has been associated with bronchial hyperresponsiveness and loss of bronchoprotection in asthma patients, a proasthmatic phenotype that increases the risk of asthma exacerbation during long‐term use of these drugs (Spitzer et al ., 1992; Cates et al ., 2008).…”

Cardiovascular mortality and morbidity in chronic obstructive pulmonary disease: the impact of bronchodilator treatment

“…Meta‐analyses of LABA use in asthma found an increase in non‐fatal serious events, 48,49 but not for cardiovascular mortality or non‐fatal cardiovascular events. In contrast, LABA use in COPD has been associated with an increased respiratory mortality, 50 although the accuracy of the cause of death was uncertain and the authors comment that confounding by cardiovascular deaths was possible.…”

Primary Care of the Patient with Asthma

“…They are not recommended as monotherapy in asthma, however, because of a slightly increased risk for serious adverse events, including death or severe asthma exacerbations. 53,54 Combination inhaler products that use a moderatedose ICS in addition to a LABA, such as budesonide/formoterol 80/4.5 or fluticasone 250 mg/salmeterol 50 mg, are safer and more effective than monotherapy with a LABA 55 and should be prescribed for those with symptoms that persist despite at least moderate-dose ICS. 35 …”