ED patients with acute asthma are an important subgroup of asthma patients with relatively high risk of adverse outcomes. Given the continued concerns over the safety of chronic LABA therapy, it is important to examine this issue in this unique population. In our large multicenter prospective cohort of ED patients with acute asthma, we found an increased risk of hospitalization among patients on salmeterol monotherapy, but no apparent increased risk among patients on combination ICS-salmeterol therapy. We used multivariable logistic regression to control for the different sociodemographic, chronic asthma, and acute asthma factors between the groups. This is a common statistical method used in observational studies to adjust for potential confounders.25
An important observation is that prior to adjustment, the combination ICS-salmeterol therapy patients (Group D) appeared to have the highest risk of hospitalization; however after adjustment, the majority of this group’s hospitalization risk was explained by confounding factors. Conversely, even after adjusting for confounders, the salmeterol monotherapy patients (Group B) still showed a higher risk of hospitalization. To our knowledge, only one prior study has examined this issue but was limited by small sample size (n=114) at a single site, lacked adjustment for potential confounders, and lacked patients on ICS therapy.26
Thus, our study adds novel data to the ongoing debate from the ED setting.
The consistent message about LABA – from the Salmeterol Multicenter Asthma Research Trial (SMART) trial11
and four subsequent meta-analyses9, 10, 12, 27
– is that LABA increases the risk of fatal asthma as compared to treatment with placebo. Furthermore, two of three meta-analyses showed that risk of asthma-related hospitalization is also increased on LABA compared to placebo.9, 10, 12
Although these risks are largely attributed to the effects of LABA monotherapy, it is important to recognize that the majority of trials allowed patients to be on concurrent baseline ICS therapy, including the SMART trial which heavily weighted all subsequent meta-analyses.9
Post-hoc analysis of SMART data and one meta-analysis do support that LABA monotherapy is the likely culprit for fatal asthma,11, 27
however such conclusions based on secondary analyses should be accepted cautiously. Additionally, asthma-related hospitalization has not been similarly examined. Common hypotheses to explain why chronic LABA monotherapy may increase asthma-related hospitalizations include tolerance to rescue SABA therapy, increased sensitivity to bronchoconstricting stimuli, and masking of acute asthma symptoms resulting in delayed presentation.7, 13–15
These proposed mechanisms would lead to decreased asthma control in the ED setting, necessitating hospitalization for further management. Indeed, when we focused on ED patients with acute asthma, we also found an increased risk of hospitalization in patients on salmeterol monotherapy.
More controversial is the question of whether combination therapy with ICS can protect against the adverse effects of LABA.6, 7
Recent meta-analyses have reported no risk difference in asthma-related hospitalization between combination ICS-LABA therapy compared to ICS monotherapy.9, 12, 28–32
Likewise, in our ED cohort, patients on chronic combination ICS-salmeterol therapy did not experience increased risk of asthma-related hospitalization, as was found in the salmeterol monotherapy group. Importantly, when we changed our reference group to ICS monotherapy, combination ICS-salmeterol therapy continued to show no difference in the risk of hospitalization. Therefore, it appears that the apparently protective effects of ICS in combination therapy, as reported in several population-based asthma outpatient studies,9, 12, 28–32
also applies to high-risk ED patients with acute asthma.
Two recent meta-analyses have suggested a beneficial effect of combination ICS-LABA therapy compared to ICS monotherapy.9, 28
In 2008, Jaeschke and colleagues reported a meta-analysis that looked at 62 RCTs.28
Only 34 RCTs had results on asthma-related nonfatal hospitalization and of these 18 RCTs used similar baseline ICS dosages. They found a trend towards a beneficial effect of combination ICS-LABA therapy, both when they looked at similar dosages of baseline ICS between groups (OR 0.66; 95%CI 0.41–1.05) and differing dosages of ICS (OR 0.74; 95%CI 0.53–1.03). In a 2009 meta-analysis, Rodrigo and colleagues found 57 RCTs comparing combination ICS-LABA therapy versus ICS monotherapy, of which 25 RCTs reported outcomes for asthma-related hospitalizations.9
They found a significant beneficial effect of combination therapy for risk of asthma-related hospitalization (RR 0.58; 95%CI 0.45–0.74).
While these two meta-analyses9, 28
suggest a potential beneficial effect of combination therapy, our study did not show a similar trend or difference. It could be that our study was underpowered to detect this difference. Additionally the differences in our population of acute asthma patients compared to the asthma outpatients in RCTs may be important. In the setting of acute asthma, it could be possible that no additional benefit of combination therapy exists, but that the benefit actually resides in the prevention rather than the treatment of acute asthma episodes. These possibilities merit further study.
Regardless, current recommendations of the National Asthma Education and Prevention Program (NAEPP) state that LABA should not be used as monotherapy and should only be added to concurrent ICS therapy in the setting of moderate-to-severe persistent asthma.4
Recent meta-analyses have provided much evidence in support of this approach in the chronic management of asthma. Our study adds evidence on the safety of combination ICS-salmeterol therapy in a large population of ED patients with acute asthma and suggests that the NAEPP guidelines remain relevant in this important setting.
Our study was ED-based, and not population-based, so care must be taken when generalizing these results to other clinical settings or to the clinical course of less severe episodes of acute asthma. However, given that the concern about salmeterol relates to an increased risk of fatal and near-fatal events, we believe that the ED setting provides valuable insight into this contentious issue. Additionally, our analysis is based on observational studies, not randomized trials. While we used multivariable modeling techniques and stratification to control for observed differences in acute and chronic asthma severity, there is always the possibility of unmeasured confounding.33
The final multivariable model, however, had a relatively high area-under-the-curve (0.86) and did eliminate the apparent increased risk of those on ICS and combination ICS-salmeterol therapy. We did not collect data on forced expiratory volume in one second or daytime and nighttime symptoms. Our study may have enrolled patients who were not optimized on their chronic asthma medications or not on appropriate preventative medications. This would likely result in a higher severity of acute asthma, thus we anticipate bias related to this subset of patients would be minimized by our adjusting for acute asthma severity. It is often difficult to distinguish asthma from other chronic obstructive pulmonary diseases, thus it is possible patients were misclassified as asthma in our study; however, using a younger age range for our inclusion criteria would minimize this limitation and our adjusting for age and smoking status would further minimize significant bias. Lastly, we recognize that our study did not have a standardized treatment protocol or admission criteria. This could result in increased variability in our measured outcome or add bias to our results. However, increased variability would favor a null result, while bias was minimized by adjusting for severity and acute ED management.
ED patients with acute asthma represent a high risk population, and we examined the safety of LABA in this unique setting. Our study shows that LABA monotherapy is associated with an increased risk of asthma-related hospitalization, while concurrent chronic therapy with ICS appears to protect against this risk. While our findings remains consistent with prior studies, we provide further evidence that combination ICS-LABA therapy remains safe even in high risk acute asthma. Hospitalization remains an important outcome in acute asthma for its relation to acute asthma severity, including response to emergency treatment; its association with future morbidity and mortality; and its implication for healthcare costs. Our study results from the ED setting reinforce the importance and safety of following NAEPP guidelines for the chronic management of asthma.