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Original Article
A BS T R AC T
BACKGROUND
The safe and appropriate use of long-acting beta-agonists (LABAs) for the treat- From Respiratory Clinical Development
ment of asthma has been widely debated. In two large clinical trials, investigators (D.A.S., I.H.R., A.M.Y., C.M.P., K.S.B.,
S.J.P.) and Research and Development,
found a potential risk of serious asthma-related events associated with LABAs. Clinical Platforms and Sciences, Clinical
This study was designed to evaluate the risk of administering the LABA salme- Statistics (K.M.K., A.H.E.), GlaxoSmith-
terol in combination with an inhaled glucocorticoid, fluticasone propionate. Kline, Durham, NC. Address reprint re-
quests to Dr. Stempel at Respiratory
Clinical Development, GlaxoSmithKline,
METHODS 5 Moore Dr., P.O. Box 13398, Research
In this multicenter, randomized, double-blind trial, adolescent and adult patients Triangle Park, Durham, NC 27709, or at
(age, 12 years) with persistent asthma were assigned to receive either fluticasone david.a.stempel@gsk.com.
with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of *A complete list of investigators in the
a severe asthma exacerbation in the year before randomization but not during the AUSTRI trial is provided in the Supple-
mentary Appendix, available at NEJM
previous month. Patients were excluded from the trial if they had a history of life- .org.
threatening or unstable asthma. The primary safety end point was the first serious
This article was published on March 6,
asthma-related event (death, endotracheal intubation, or hospitalization). Non 2016, at NEJM.org.
inferiority of fluticasonesalmeterol to fluticasone alone was defined as an upper
DOI: 10.1056/NEJMoa1511049
boundary of the 95% confidence interval for the risk of the primary safety end point Copyright 2016 Massachusetts Medical Society.
of less than 2.0. The efficacy end point was the first severe asthma exacerbation.
RESULTS
Of 11,679 patients who were enrolled, 67 had 74 serious asthma-related events,
with 36 events in 34 patients in the fluticasonesalmeterol group and 38 events in
33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-
related event in the fluticasonesalmeterol group was 1.03 (95% confidence inter-
val [CI], 0.64 to 1.66), and noninferiority was achieved (P=0.003). There were no
asthma-related deaths; 2 patients in the fluticasone-only group underwent asthma-
related intubation. The risk of a severe asthma exacerbation was 21% lower in the
fluticasonesalmeterol group than in the fluticasone-only group (hazard ratio,
0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring
in 480 of 5834 patients (8%) in the fluticasonesalmeterol group, as compared
with 597 of 5845 patients (10%) in the fluticasone-only group (P<0.001).
CONCLUSIONS
Patients who received salmeterol in a fixed-dose combination with fluticasone did
not have a significantly higher risk of serious asthma-related events than did those
who received fluticasone alone. Patients receiving fluticasonesalmeterol had
fewer severe asthma exacerbations than did those in the fluticasone-only group.
(AUSTRI ClinicalTrials.gov number, NCT01475721.)
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The n e w e ng l a n d j o u r na l of m e dic i n e
T
he safe and appropriate use of ances in the rates of asthma-related hospitaliza-
short-acting beta-agonists (SABAs) and tion when salmeterol was dispensed in a fixed-
long-acting beta-agonists (LABAs) for the dose combination with fluticasone propionate.9,10
treatment of asthma has been widely debated.1 In 2010, the FDA requested that each of the
In early reports, SABAs were associated with an four manufacturers undertake a large prospec-
increased risk of asthma-related death.2,3 In the tive trial to evaluate whether a LABA added to an
1990s, analyses suggested that high use of SABAs inhaled glucocorticoid would be noninferior to
(>1.5 to 2 canisters per month) might increase an inhaled glucocorticoid alone with respect to
the risk of death or near-fatal asthma.4-6 In one the risk of a serious asthma-related event (hospi-
of these studies, the authors postulated that talization, endotracheal intubation, or death).11 The
high use of SABAs was either a marker of poor- composite of serious asthma-related events was
ly controlled asthma or a toxic effect of the selected since asthma-related deaths are rare in
medications or their vehicles.6 clinical trials.
Two large clinical trials, the Serevent Nation- We designed this prospective, multicenter,
wide Surveillance (SNS) trial7 and the Salmeterol randomized, double-blind trial (AUSTRI) with a
Multicenter Asthma Research Trial (SMART),8 primary objective of establishing whether the risk
were designed to address whether regular use of of serious asthma-related events would be higher
the LABA salmeterol was associated with an in- when salmeterol was used concomitantly with
creased risk of serious asthma events. At that time, fluticasone as a fixed-dose combination (flutica-
inhaled glucocorticoids were not part of routine sonesalmeterol) than if fluticasone was used
asthma care. Although the SNS trial showed sig- alone. A secondary objective was to evaluate
nificantly fewer withdrawals because of worsen- whether fluticasonesalmeterol was superior to
ing asthma with salmeterol than with salbutamol, fluticasone with respect to prespecified measures
the rate of asthma-related deaths was higher of efficacy.
among salmeterol-treated patients, although the
difference was not significant.7 In SMART, more Me thods
patients receiving salmeterol than receiving pla-
cebo died, both from respiratory-related events Trial Design and Oversight
(24 vs. 11) and from asthma-related events (13 vs. From November 2011 through June 2015, we en-
3).8 This risk was greater among black patients rolled adolescent and adult patients (age, 12 years)
than among white patients.8 Although 47% of with moderate-to-severe asthma at 710 centers
the patients were receiving inhaled glucocorticoids in 33 countries. All the patients attended a screen-
at baseline, SMART was not designed to address ing and randomization visit, which was followed
whether concurrent use of inhaled glucocorti- by a 26-week active treatment period and a 1-week
coids altered the risk.8 follow-up period (Fig. S1 in the Supplementary
In 2008, the Food and Drug Administration Appendix, available with the full text of this ar-
(FDA) requested that the four manufacturers of ticle at NEJM.org).
LABA-containing medications for the treatment Members of a common joint oversight steer-
of asthma assess the rates of asthma-related death, ing committee, a joint adjudication committee
intubation, and hospitalization by analyzing the (which was responsible for uniform determina-
data in all their studies of LABAs. In response, tion of asthma-relatedness for study end points),
GlaxoSmithKline, the manufacturer of salmeterol, and a joint data and safety monitoring committee
compared data regarding salmeterol with non- were charged with ensuring responsible conduct
LABA data in a meta-analysis9; this meta-analy- of the trial and the safety of all the patients. An
sis showed higher rates of asthma-related death independent, trial-specific data and safety moni-
and hospitalization among patients receiving toring committee reviewed trial-specific safety
salmeterol, with inhaled glucocorticoids dis- data for patients every 6 months, with one planned,
pensed in a separate inhaler (i.e., inhaled gluco- formal interim statistical analysis performed
corticoids were not part of the treatment proto- after approximately half the expected 87 events
col and may or may not have been used), than had occurred (see the trial protocol, available at
among patients receiving non-LABA treatment.9 NEJM.org).
There were no asthma-related deaths or imbal- Scientific oversight of the trial was provided
2 n engl j mednejm.org
by employees of GlaxoSmithKline, including the Patients were randomly assigned in a 1:1 ratio
authors, who were collectively responsible for within stratification groups to receive a combi-
the design and conduct of the trial. The joint nation of fluticasone propionate and salmeterol
steering committee and the FDA provided advice (at a dose of 100 g of fluticasone and 50 g of
on the trial, which was harmonized with trials salmeterol, 250 g and 50 g, respectively, or
conducted by the other three manufacturers of 500 g and 50 g, respectively) or fluticasone
LABA-containing medications. The initial draft propionate alone (at a dose of 100 g, 250 g,
of the manuscript was written by the first au- or 500 g), administered twice daily in a masked
thor, and all the authors worked collaboratively DISKUS dry-powder inhaler (GlaxoSmithKline).
to prepare the final content. Editorial support Study treatment was double-blinded with respect
was provided by a professional medical writer to fluticasonesalmeterol versus fluticasone alone
who was paid by GlaxoSmithKline. Statistical but not with respect to the dose of inhaled glu-
analyses were performed by employees of Glaxo- cocorticoid. All treatments were presented in
SmithKline and PAREXEL International. All the identical packaging. Open-label rescue albuterol
authors had full access to the data and vouch for or salbutamol administered through a metered-
the accuracy and completeness of all data and dose inhaler was also supplied to all patients.
analyses and agreed to the submission of the
manuscript for publication. Study End Points
Ethical approval was obtained from the rele- Safety
vant ethics committee or institutional review board The primary safety end point was the first seri-
at each site. The trial was conducted in accor- ous asthma-related event, a composite end point
dance with Good Clinical Practice guidelines and that included death, endotracheal intubation, and
the provisions of the Declaration of Helsinki. hospitalization. Events were reviewed by mem-
bers of the joint adjudication committee who were
Trial Population unaware of the study-group assignments. All hos-
Eligible patients had at least a 1-year history of pitalization events underwent initial screening by a
asthma,12,13 required daily medications for asth- member of the joint adjudication committee,
ma control, and had received treatment with sys- and if the patients condition was considered to
temic glucocorticoids for an asthma exacerbation be potentially asthma-related, a complete adjudi-
or had been hospitalized for an asthma exacerba- cation followed. All intubations and deaths were
tion during the previous 12 months, with the fully adjudicated.
exclusion of the 30 days before randomization. All nonserious adverse events leading to with-
Patients were excluded from the study if they drawal from the trial and all serious adverse
had a history of life-threatening asthma, cigarette events were documented. The vital status and
smoking for more than 10 pack-years, or unstable mortality of all patients who received at least one
asthma. (A detailed description of the trial criteria dose of a study drug were assessed after the
is provided in the Methods section in the Supple- 6-month trial period.
mentary Appendix.) All the patients or their legal
guardians provided written informed consent. Efficacy
The main efficacy end point was the first severe
Study Randomization and Treatments asthma exacerbation, which was defined as asth-
Randomization was performed with the use of ma deterioration that led to the use of systemic
an interactive voiceresponse system, with strat- glucocorticoids for at least 3 days or an asthma-
ification of patients in six groups according to related hospitalization or emergency department
the patients current asthma medications and as- visit that led to the use of systemic glucocorti-
sessment of asthma control (Table S1 in the Sup- coids.15 A secondary measure of efficacy was the
plementary Appendix). Asthma control was as- use of rescue albuterol or salbutamol.
sessed at screening and during office visits with
the use of the Asthma Control Questionnaire 6 Statistical Analysis
(ACQ-6), on which asthma symptoms are rated The primary safety objective was assessed by
on a scale of 0 to 6, with higher values indicat- means of a stratified Cox proportional-hazards
ing worse symptoms.14 regression model of the time until the first seri-
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The n e w e ng l a n d j o u r na l of m e dic i n e
ous asthma-related outcome, with a term for tient stopped the study drug. Four efficacy sub-
randomized treatment (fluticasonesalmeterol groups that were classified according to the level
or fluticasone alone) and with the randomiza- of asthma control at baseline (controlled or not
tion stratum according to the asthma treatment controlled) and previous asthma therapy (in-
being received and the level of asthma control at haled glucocorticoids or inhaled glucocorticoids
baseline as the stratification factor. Noninferior- plus LABA) were prespecified for analysis (Table
ity of fluticasonesalmeterol to fluticasone alone S2 in the Supplementary Appendix).
was defined as an upper boundary of the 95%
confidence interval for the risk of the primary R e sult s
safety end point of less than 2.0. In the two treat-
ment groups, data from the three dose strata were Trial Population
combined. A total of 11,751 patients underwent randomiza-
We used a Cox proportional-hazards regres- tion at 694 of the 710 centers that participated
sion model to test the main efficacy end point. in the trial. Of these patients, 72 (0.6%) did not
The study was not powered to allow formal sta- receive a dose of a study drug, so 11,679 patients
tistical comparison or evaluation of fluticasone were included in the intention-to-treat popula-
salmeterol versus fluticasone alone in subgroups. tion (5834 in the fluticasonesalmeterol group and
However, for the key subgroups of age and race, 5845 in the fluticasone-only group) (Fig.1, and
descriptive analyses were performed, and results Table S3 in the Supplementary Appendix). The
are expressed as hazard ratios and 95% confi- demographic characteristics of the patients were
dence intervals. similar in the two groups (Table1). The median
In calculating the sample size for the primary rate of adherence to study medications (as deter-
safety end point, we assumed that the rate in the mined by the dose counter in the DISKUS device)
fluticasone-only group would be 0.0075 patients was 95.1% in each of the two groups.
with an event during the 26-week trial. The sample
size was adjusted to accommodate one interim Safety
statistical analysis when approximately half the Serious Asthma-Related Events
expected number of composite end points had Among the 11,679 patients, 67 had 74 serious
occurred. We used the HaybittlePeto method for asthma-related events, with 36 events in 34 pa-
managing the alpha spending function over the tients in the fluticasonesalmeterol group and
interim analysis and the final analysis.16,17 We 38 events in 33 patients in the fluticasone-only
determined that a sample size of 11,664 partici- group (Table2). The hazard ratio for a serious
pants would allow the observation of 87 patients asthma-related event in the fluticasonesalme-
with the composite end point, which would give terol group was 1.03 (95% confidence interval [CI],
the study 90% power to show the noninferiority 0.64 to 1.66). The upper boundary of the confi-
of fluticasonesalmeterol to fluticasone alone, dence interval did not exceed 2.0; therefore,
with the use of the log-rank test, at a one-sided fluticasonesalmeterol was shown to be nonin-
alpha level of 0.025, and to reject the null hypoth- ferior to fluticasone alone (P=0.003). The Kap
esis that the risk associated with fluticasone lanMeier curve for the primary safety end point
salmeterol, as compared with fluticasone alone, is shown in Figure2.
would be greater than the noninferiority margin. There were no asthma-related deaths in either
The primary analysis was performed in the group. One or more asthma-related hospitaliza-
intention-to-treat population, which included all tions were reported in 34 patients in the flutica-
the patients who had undergone randomization sonesalmeterol group and in 33 patients in
and received at least one dose of fluticasonesal- the fluticasone-only group (with a total of 36
meterol or fluticasone alone. For the primary asthma-related hospitalizations in each group)
analysis, the data included composite events that (Table2). There were no significant differences
occurred within 6 months after the first dose or in the rates of asthma-related hospitalization
7 days after the last dose of a study drug, which- according to age group (12 to 17 years, 18 to 64
ever interval from randomization was greater. A years, and >64 years) or race (white, black, or
modified intention-to-treat analysis included other), although the trial was not powered to
only data collected up to 7 days after each pa- detect noninferiority in these subgroups (Table
4 n engl j mednejm.org
947 Were withdrawn from study 1066 Were withdrawn from study
treatment treatment
102 Had adverse event 96 Had adverse event
66 Had asthma exacerbations 84 Had asthma exacerbations
21 Had lack of efficacy 50 Had lack of efficacy
48 Were lost to follow-up 37 Were lost to follow-up
130 Had protocol deviation 147 Had protocol deviation
580 Withdrew 652 Withdrew
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6 n engl j mednejm.org
Hazard Ratio
Subgroup Severe Asthma Exacerbation (95% CI) P Value
Fluticasone Fluticasone
Salmeterol Alone
no./total no. (%)
Asthma control
Not well controlled on previous inhaled glucocorticoid 91/1405 (6) 106/1398 (8) 0.83 (0.631.10) 0.20
or non-LABA therapy
Not well controlled on previous inhaled glucocorticoid 102/1016 (10) 124/1040 (12) 0.84 (0.651.09) 0.19
plus LABA therapy
Well controlled on previous inhaled glucocorticoid 239/2652 (9) 304/2663 (11) 0.76 (0.650.91) 0.002
plus LABA therapy
Well controlled on previous inhaled glucocorticoid 38/612 (6) 54/608 (9) 0.68 (0.451.03) 0.07
therapy
Age
1217 yr 42/615 (7) 64/615 (10) 0.65 (0.440.95) 0.03
1864 yr 386/4576 (8) 469/4605 (10) 0.81 (0.710.93) 0.002
>64 yr 52/643 (8) 64/625 (10) 0.78 (0.541.12) 0.17
* The analysis was performed in the modified intention-to-treat population, which included all the patients in the intention-to-treat population
for whom data were available 7 days after the last dose of a trial medication was administered.
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The n e w e ng l a n d j o u r na l of m e dic i n e
time that earlier trials were conducted and be- were included only if they had a history of a se-
cause the use of inhaled glucocorticoids was not vere exacerbation in the 12 months before ran-
controlled in the earlier trials. No patients who domization.24,27
were treated with fluticasonesalmeterol or Studies have shown that routine use of SABAs
fluticasone alone in our trial died from asthma- or LABAs without inhaled glucocorticoids in-
related causes, which provides further evidence creases the risk of serious and potentially fatal
that the use of fluticasonesalmeterol does not outcomes among patients with asthma.1-5,7-9 The
increase the risk of asthma-related death. frequent use of SABAs is the hallmark of uncon-
In our trial, the risk of asthma-related hospi- trolled asthma, and escalation in therapy with
talization was low, approximately 1 per 100 pa- antiinflammatory agents such as inhaled gluco-
tient-years, and corresponds to low incidences corticoids is recommended.12 In addition, LABA
that were observed in other studies involving monotherapy may mask underlying disease by
similar populations.9,18,21,22 Since the patients in providing a temporary reduction in symptoms
our trial were at high risk for asthma-related but ultimately placing patients at risk for serious
events, the low incidence of serious asthma- exacerbations.28 However, the risks appear to be
related events suggests that treatment adherence mitigated when beta-agonists are reliably used
may be key to controlling asthma. The associa- with concomitant inhaled glucocorticoids, includ-
tion between these events and fluticasonesal- ing with the fixed-dose combination of flutica-
meterol that we observed is consistent with that sonesalmeterol.7,9,10,18
in a nested casecontrol analysis of inhaled Limitations of this trial include its relatively
glucocorticoids plus LABAs, as compared with short duration of 26 weeks and the infrequent
inhaled glucocorticoids alone, in which the rate occurrence of serious asthma-related events. Also,
ratio for asthma-related hospitalization among we enrolled patients with moderate-to-severe
patients receiving inhaled glucocorticoids plus asthma, and the results may not be applicable to
LABAs, as compared with those receiving in- all patients with asthma. For example, since
haled glucocorticoids alone, was 1.14 (95% CI, patients with a history of life-threatening or un-
0.93 to 1.41).23 stable asthma were excluded from the study, our
Studies and reviews that have evaluated the results cannot be extrapolated to such patients.
safety of SABAs and LABAs have included a The study was designed with FDA guidance, and
discussion of possible causes of the observed we assessed a composite end point of serious
increase in the risk of asthma-related death and asthma-related events to help address the infre-
have noted a concern about whether the risk quent occurrence of asthma-related death and
was greater among specific age or racial intubation. In addition, although we designed the
groups.1,8,10,18-20,24-26 Data from our trial do not trial as a real world analysis, adherence was
support hypotheses that specific age or racial high, which may not always occur in real-world
groups are at greater risk when beta-agonists are clinical practice. The extent of underlying inflam-
used concurrently with inhaled glucocorticoids. matory disease in each patient was not measured,
Another important finding in our trial is that a factor that may have influenced the results; the
the risk of a severe asthma exacerbation was 21% prespecified efficacy subgroups were included to
lower among patients who were treated with partly counterbalance this limitation.
fluticasonesalmeterol than among those treated In conclusion, we found that among patients
with fluticasone alone. The difference was most with moderate-to-severe asthma, serious asthma-
prominent among adolescents, in whom the risk related events occurred with similar frequency
was 35% lower. Among patients in whom asth- among those receiving 26 weeks of treatment with
ma was well controlled on a previous regimen of fluticasonesalmeterol and those receiving fluti-
inhaled glucocorticoids plus LABAs, the risk of casone alone, which showed the noninferiority
a severe asthma exacerbation was 24% lower in of the fixed-dose combination to fluticasone
the fluticasonesalmeterol group than in the alone. The clinical benefits of fluticasonesal-
fluticasone-only group. These effect sizes are con- meterol were significant, with a 21% lower risk
sistent with a previous meta-analysis that com- of a severe asthma exacerbation among patients
pared fluticasonesalmeterol with fluticasone who received that therapy than among those who
alone18 and with other trials in which patients received fluticasone alone.
8 n engl j mednejm.org
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