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Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database Syst Rev. 2010;(4):CD005533.

Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med. 2006;144(12):904-912.

Cates CJ, Wieland LS, Oleszczuk M, Kew KM. Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2014;(2):CD010314.

Study Population: Adult patients with asthma of differing severities

Efficacy Endpoints

Asthma-related quality of life, asthma exacerbation requiring oral steroids, exacerbation requiring hospitalization, life threatening asthma-related event (death or intubation), all-cause death

Harm Endpoints

Death, asthma-related death, life threatening asthma event

Narrative

Long-acting beta-agonists (LABAs) relax smooth muscle in asthmatic lungs, potentially preventing attacks and improving symptoms. While inhaled corticosteroids (ICS) are first-line ‘controllers’, adding LABAs to the regimen is common. Unfortunately, the 2006 ‘SMART’ trial showed that LABAs increase severe attacks and asthma-related deaths.1 However there remains debate on whether partnering LABAs with ICS neutralizes this risk. The FDA recently removed its black box warning2 for LABAs on the basis of a meta-analysis, and most guidelines suggest adding them for improved control. The common alternative involves increasing the dose of ICS. This summary examines adding LABAs to ICS versus increasing ICS dose for improved control.

The Cochrane review discussed here examined 48 trials of >33,000 asthmatics on ICS randomized to add a LABA or increase the ICS dose.3 Adding LABAs did not reduce hospitalizations, deaths, or severe attacks. However, it did reduce asthma exacerbations requiring 3-5 days of oral corticosteroids (relative risk 0.9, 0.95CI: 0.8-0.98; absolute risk difference [ARD] 1.5%; NNT: 73). For those at highest risk (patients with an estimated 20% risk of an exacerbation during a 12-week study period) the ARD was 2.2% (NNT: 45), while for those at lower risk (1% risk of exacerbation during the study period) the ARD was just 0.15% (NNT: 673). In other words, those with more severe asthma were more likely to benefit. LABAs also improved symptoms slightly, however asthma-related quality of life was unchanged.2

The issue of whether LABAs increase asthma deaths or near fatal asthma events when partnered with ICS is complex. Different topic reviews and meta-analyses designed to answer this question offer different answers, although the differences are mostly based on statistical significance (relative risks of 1.4 or higher for fatal and near fatal events with the presence of a LABA are seen across virtually all reviews). The review by Salpeter et al., for instance, notes statistically increased fatalities and near fatalities even when combined with steroids,4 while a 2014 Cochrane review finds a non-statistically significant odds ratio of 1.4 (95% CI: 0.6-3.4).1^, 5

Because of this uncertainty, in 2010 the FDA commissioned four LABA manufacturers to conduct safety trials pitting ICS alone against LABA plus ICS. In a meta-analysis of 36,000 subjects in these four trials there were just 2 asthma deaths (LABA group) and 3 intubations (1 LABA, 2 control), yielding a relative risk of 1.5 (95% CI: 0.3-9.0) for this endpoint.6

Caveats

There are many reviews of LABA safety and efficacy. We focus on one clinical choice, increasing the steroid versus adding a LABA. However other comparisons may be more useful at times, for instance when steroid doses are maximized, or other options (e.g. anticholinergics, leukotriene inhibitors) fail.7^, 8

Available data are imperfect for the answers we seek. The 2006 SMART trial was stopped early (both because of harms and slow enrollment) and was designed to address dangers due to LABAs generally. It was not designed specifically to test whether those dangers remain when LABAs are partnered with ICS. Moreover, many reviews fail to control for ICS dose when showing this comparison. This makes interpretation tricky since ICS improves outcomes in a dose-dependent fashion—thus when a group on LABAs + ICS suffers more life-threatening events than a group taking double-dose ICS, is this because LABAs increased events or because the higher ICS dose decreased them?

One large 2012 review catalogs prior reviews and performs meta-analyses that control for ICS and other confounders. This ‘meta-review’ finds higher death and intubation rates with LABA plus ICS than ICS-alone (Table 3),9 but the differences are statistically nonsignificant. Citing mostly unpublished drug company trials, in which few deaths or intubations occurred in either group, the authors conclude partnering LABAs with ICS may neutralize the dangers.9

Importantly, the benefits of LABAs for symptomatic relief were statistically significant but clinically questionable compared to increasing ICS dose, and conferred no advantage in asthma-related quality of life. However, one potential advantage of using LABAs remains: less ICS exposure, which could lead to less inhibition of growth in children.

On the safety of LABAs when partnered with ICS, however, we believe the studies commissioned by the FDA enrolled the wrong cohort. The purpose of commissioning the trials was to evaluate if combining LABAs with ICS prevents the established increase in fatal and near fatal events caused by LABAs. The 2006 SMART trial (similarly commissioned to address concerns about LABA dangers) saw 86 fatal or near fatal events among 26,000 subjects. This robust number of events made it possible to detect an important difference between groups.1 The 2018 meta-analysis of four FDA studies, however, reports just 5 fatal or near fatal events in 36,000 trial subjects, suggesting a near zero risk cohort.5 The FDA-commissioned trials therefore studied a population in whom it was not possible to answer the question they were commissioned to answer—in a cohort where virtually no one dies, it is not possible to reduce deaths.

In addition, and ironically, neither an important benefit nor an important harm was possible in a cohort at such a low risk. Adding LABAs in this cohort resulted in a less than 2% reduction in minor exacerbations requiring 3-5 days of oral steroids.5 However the ICS dose was kept the same in both groups, whether LABAs were added or not. Therefore, even the small benefit would almost certainly have been smaller, or disappeared, if the ICS dose had been increased in the control group. Meanwhile, the higher risk asthmatics enrolled in the SMART trial are the group most likely to see meaningful benefits since, as data consistently show, the higher the risk, the greater the benefit from LABAs. The finding of little or no meaningful benefit in the FDA trials is consistent with a voluminous body of literature, summarized above, showing that patients at low risk see virtually no meaningful benefit.

Of note, the many trials performed on subjects at near zero risk for asthma-related death or intubation may help explain the differing conclusions from safety reviews. Earlier reviews found statistically significant differences while later reviews often did not, despite relative risks remaining the same (typically 1.4 to 1.5). However instead of 1 in every 350 subjects experiencing a life-threatening event (as in the SMART trial),1 in the more recent trials life-threatening events were 20-fold less common, or roughly 1 in 7000 subjects.5 In other words, while higher rates of fatal and near fatal events persisted, they became statistically nonsignificant as participants in later trials virtually never had an event. If, for comparison, the FDA-commissioned trials had enrolled subjects similar to those in the SMART trial, most likely more than 100 events would have occurred—enough for a meaningful statistical analysis.

Meanwhile, and perhaps more concerning, it is the higher risk group who benefits most from LABAs, for whom guidelines recommend LABAs, and who are almost universally prescribed LABAs. This issue is critical for real world application: one commonly cited study suggests <5% of asthmatics in the community would meet eligibility criteria for most randomized trials of interventions for asthma.9 The FDA trial cohorts support this notion: patients at higher risk, i.e. those typically prescribed LABAs in the community, were not enrolled. Instead the researchers excluded any patient with ‘a history of life-threatening asthma’, ‘unstable asthma’, and anyone with multiple hospitalizations. These are the patients most consistently prescribed LABAs in practice, and the 2006 SMART trial made no such exclusions.

An editorial accompanying the 2018 meta-analysis of FDA trials declares LABAs safe. The editorialists cite equal hospitalizations between groups, and note the FDA removed its black box warning based on this finding.2 However, in the 2006 SMART trial hospitalizations were also the same between groups.1 The more recent trials existed solely to address dangers established in the SMART trial, but increased hospitalization was not one of them. Declaring the drugs safe on this basis, without resolving whether LABAs increase deaths in the population most commonly taking them, seems unfounded.

The widespread use of LABAs today is based entirely on a theory that when paired with ICS the increase in fatal and near fatal events caused by LABAs disappear. But in the only trial with adequate power to address this theory LABA dangers were present whether or not patients were also prescribed an ICS inhaler (SMART trial, see Table 8).1 While adherence to both inhalers was not tracked, leaving much room for uncertainty, this finding highlights a concerning fact: the only study of LABAs adequately powered to detect life threatening harms presents a direct challenge to the theory that ICS is protective.

Finally, all-cause mortality is a better outcome than asthma-related deaths but is often not reported. Moreover, using different endpoints from these trials is fraught, and selecting the right review for reporting the estimates is difficult, which is why we offer a range. Our NNH of 1430 is based on one estimate. Which estimate is the truth is anyone’s guess.

We have chosen to designate the color recommendation of RED because of a small potential benefit of questionable clinical utility (<2%, avoiding a brief course of oral steroids), no quality of life benefit, and the lingering possibility of a fatal harm. We considered BLACK (harms>benefits) however there is uncertainty on harms, and it remains possible that ICS have a protective effect against the harms that has not yet been found. A proper trial would require enrollment of real world patients at genuine risk for a fatal asthma event, and we hope to see such a trial in the future. We recognize this color designation and interpretation are at odds with some clinical guidelines, and the FDA’s recent decision, as well as common practice. We hope providers and patients can use this to discuss these issues and come to helpful, informed conclusions.

Author

Shahriar Zehtabchi, MD
Supervising Editors: Allan Wolfson, MD

Published/Updated

April 30, 2021