Long-Acting Asthma Drug With Inhaled Steroid Safe in Two Trials

Marcia Frellick

September 01, 2016

Two large randomized trials demonstrate that adding a long-acting β-agonist (LABA) to an inhaled corticosteroid does not add risk for children and adults with moderate to severe asthma.

Questions regarding the safety of LABAs have been debated after previous trials delivered conflicting messages, leading the US Food and Drug Administration (FDA) to issue a black-box warning on the drugs.

In one of the two new trials, funded by AstraZeneca, the combination of long-acting formoterol added to budesonide (Symbicort) lowered the risk for an asthma exacerbation in people age 12 years or older by 16.5% (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.74 - 0.94; P = .002), and the combination was associated with a risk for serious asthma-related events similar to that seen with budesonide alone (HR, 1.07; 95% CI, 0.70 - 1.65).

In the other trial, funded by GlaxoSmithKline, the LABA salmeterol in a fixed-dose combination with fluticasone (Advair) had a risk for serious asthma-related events similar to the risk with fluticasone alone among children aged 4 to 11 years (HR, 1.28; 95% CI, 0.73 - 2.27), which showed the noninferiority of fluticasone–salmeterol (P = .006). However, there was also no significant difference between the two groups in the efficacy primary endpoint of time-to-event analysis for first severe asthma exacerbation (hazard ratio, 0.86; 95% CI, 0.73 to 1.01).

The results of both trials were published online August 31 in the New England Journal of Medicine.

No Higher Risk Is Reassuring

Joe Zein, MD, from the Department of Pulmonary Medicine at Cleveland Clinic in Ohio, who was not involved in either study, said, "Now…if I have an asthmatic who is not very, very sick, I'm reassured that if I give him a long-acting β-agonist, I am not going to put him at higher risk."

Dr Zein said he still has to explain the black-box warning to patients and said the FDA will have to decide whether to remove that warning on the basis of these results and those not yet reported.

What still remains to be tested, he said, is whether LABAs would be safe for the "super-sick" — for instance, those requiring more than 4 hospitalizations a year.

He notes that LABAs should be used only if the first-line corticosteroid is not working, in accordance with guidelines.

In an editorial accompanying the study on salmeterol, Andrew Bush, MB, BS, MD, from the Department of Pediatric Respiratory Medicine, Royal Brompton Hospital, London, United Kingdom, and Urs Fry, MD, PhD, from the Department of Pediatrics, University Children's Hospital Basel, Switzerland, said misuse "is increasingly creeping into practice."

"Monotherapy with a LABA in a child should be considered medical negligence," they write, "and we suggest that single LABA inhalers should carry a warning to that effect."

Most children's asthma can be controlled with inhaled, low-dose glucocorticoids if they are taken appropriately, they note. But when that doesn't work or for patients with persistent variable airflow obstruction, this new evidence that combination inhalers containing LABAs are safe is reassuring, they write.

Postmarketing Studies Were Mandated

LABAs have been an available treatment option since the 1990s, but concerns about their safety arose from two large trials — the 2007 Salmeterol Multicenter Asthma Research Trial (SMART) and the Serevent Nationwide Surveillance (SNS) trial, which found more asthma-related death and other serious outcomes among patients receiving long-acting salmeterol than among patients given the short-acting β-agonist salbutamol or placebo.

Meta-analyses followed, but because no asthma-related deaths were observed, they were considered insufficient to refute the potential risk of the previous studies.

In 2009, the FDA mandated that each of the four manufacturers of LABA-containing products in the United States conduct postmarketing safety studies comparing the effect of combined inhaled glucocorticoid and LABA therapy on frequency of serious asthma-related events (including hospitalization, intubation, or death) with that of inhaled steroids alone.

The first was the AUSTRI trial, published in May of this year. This trial showed similar results, with no data revealing increased risk for serious asthma-related events when salmeterol was added to fluticasone alone.

Salmeterol Study for Kids Age 4 to 11

Now, David A. Stempel, MD, from the Respiratory Clinical Development department at GlaxoSmithKline, and colleagues report the results of a pediatric trial comparing salmeterol with fluticasone vs fluticasone alone. The double-blind, active-comparator, 26-week trial ran from November 2011 through November 2015 at 567 trial centers in 32 countries.

Among the 6208 patients, 27 in the fluticasone–salmeterol group and 21 in the fluticasone-alone group had a serious asthma-related event (all hospitalizations). The HR with fluticasone–salmeterol vs fluticasone alone was 1.28 (95% CI, 0.73 - 2.27), which showed fluticasone–salmeterol was not inferior (P = .006).

No patients died in either treatment group.

While there was a trend for improvement in the analysis of time to first serious exacerbation with the addition of the LABA, the difference did not reach statistical significance, as mentioned above. Specifically, a total of 265 patients (8.5%) in the fluticasone–salmeterol group and 309 (10.0%) in the fluticasone-alone group had a severe asthma exacerbation (HR, 0.86; 95% CI, 0.73 - 1.01).

Results were similar in a second prespecified primary endpoint analysis that restricted the analysis to black patients. In that case, 36 of 539 (6.7%) patients in the combination group had a severe exacerbation, as did 43 of 511 (8.4%) in the fluticasone-only group (HR, 0.80; 95% CI, 0.51 - 1.24).

When asked about the lack of significant difference in efficacy endpoints, editorialist Dr Bush noted that this study was really about safety. "This study was designed to look at safety not benefit," he wrote in an email interview with Medscape Medical News. "The BADGER study [published in 2010]…showed that some patients benefit from LABAs, so there is potential benefit. As always, [physicians] need to judge on an individual basis whether a new medication is beneficial. And as we said, low dose ICS is the first line treatment not the combination."

Formoterol Study for 12 Years and Up

Meanwhile, Stephen P. Peters, MD, PhD, from Wake Forest School of Medicine in Winston-Salem, North Carolina, and colleagues enrolled patients in the formoterol trial between December 2011 and April 2015 at 534 centers in 25 countries.

In all, 11,693 patients were randomly assigned to the combination group (5846 patients) or the budesonide-alone group (5847). A serious asthma-related event occurred in 43 patients who were receiving budesonide–formoterol and in 40 patients who were receiving budesonide (HR, 1.07; 95% CI, 0.70 - 1.65). There were two asthma-related deaths, both in the combination group; one of these patients had had an asthma-related intubation.

As mentioned above, the trial showed a significant reduction in the risk for asthma exacerbation with the combination therapy vs the control.

"Middle of the Story"

Matthew Rank, MD, an allergist-immunologist and associate professor with the Mayo Clinic in Scottsdale, Arizona, agreed with Dr Zein that these results add reassurance that LABAs don't add risk in the combination medications. But he pointed out that these two trials represent "the middle of the story."

"There are plans to pool the results of all of these studies, especially for the outcome of asthma-related death, so that these risks can properly be ascertained," he told Medscape Medical News.  "Fortunately, asthma-related death is not a common outcome, and thousands of individuals need to be enrolled in multiple studies to judge the risk of ICS [inhaled corticosteroid]-LABA versus ICS for asthma-related death," Dr Rank said.

"In all three studies reported so far, only two asthma-related deaths were reported. The original projection for all studies was to have 28 asthma-related deaths from all of the studies. Of course, we will have to wait for the other studies to be reported, but it is possible that with all of the studies there may not be enough asthma-related deaths to judge the risk for this specific outcome."

Dr Peters reports nonfinancial support from AstraZeneca during the conduct of the study and personal fees from Array Biopharma, Integrity CE, Aerocrine, Boehringer Ingelheim, Experts in Asthma, Gilead Sciences, GlaxoSmithKline, Merck, Ono Pharmaceuticals, Pfizer, PPD Development, Quintiles, Sunovion, Saatchi & Saatichi, Targacept, Teva, Theron, and Sanofi-Regeneron. He has also received personal fees and other support from AstraZeneca and Novartis outside the submitted work. Coauthors report personal fees and other support from Amgen, AstraZeneca, Boehringer Ingelheim, Genentech/Roche, GlaxoSmithKline, Hanmi, Janssen/Johnson & Johnson, Knopp, MedImmune, Novartis, Pfizer, Teva, Merck Sharp & Dohme, and Sanofi-Regeneron outside the submitted work.


GlaxoSmithKline supported the study by Dr Stempel and colleagues. Dr Stempel and several coauthors are employees or former employees of and hold stock in GlaxoSmithKline. One coauthor now works at GlaxoSmithKline on contract, and another is a current employee of Parexel International working on behalf of GlaxoSmithKline. Coauthors report receiving consulting or lecture fees from Roche, AstraZeneca, Aerocrine, Daiichi-Sankyo, Boehringer Ingelheim, Genentech, Merck Novartis, Sandoz, and Teva Pharmaceuticals; serving on an advisory panel for Merck; participating in manuscript preparation and advisory boards for a study funded by Genentech; participating in the development of a study funded by Novartis; and additional grant support from Aerocrine, MedImmune, Genentech and Merck.

The editorialists, Dr Zein, and Dr Rank have disclosed no relevant financial relationships.

N Engl J Med. 2016;375:840-849, 850-860, 889-891. Stempel abstract Peters abstract Editorial

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