editorials
4.  Iravanian S, Dudley SC Jr. The renin-angiotensin-aldoste­

8.  Maggioni AP, Latini R, Carson PE, et al. Valsartan reduces

rone system (RAAS) and cardiac arrhythmias. Heart Rhythm
2008;5:Suppl:S12-S17. [Erratum, Heart Rhythm 2008;5:1499.]
5.  Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial
fibrillation with angiotensin-converting enzyme inhibitors and
angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol 2005;45:1832-9.
6.  Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan
to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 2002;106:331-6.
7.  Yin Y, Dalal D, Liu Z, et al. Prospective randomized study
comparing amiodarone vs. amiodarone plus losartan vs. amiodarone plus perindopril for the prevention of atrial fibrillation
recurrence in patients with lone paroxysmal atrial fibrillation.
Eur Heart J 2006;27:1841-6.

the incidence of atrial fibrillation in patients with heart failure:
results from the Valsartan Heart Failure Trial (Val-HeFT). Am
Heart J 2005;149:548-57.
9.  Schmieder RE, Kjeldsen SE, Julius S, McInnes GT, Zanchetti
A, Hua TA. Reduced incidence of new-onset atrial fibrillation
with angiotensin II receptor blockade: the VALUE trial. J Hypertens 2008;26:403-11.
10.  The GISSI-AF Investigators. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009;360:1606-17.
11.  Disertori M, Latini R, Maggioni AP, et al. Rationale and design of the GISSI-Atrial Fibrillation Trial: a randomized, prospective, multicentre study on the use of valsartan, an angiotensin II AT1-receptor blocker, in the prevention of atrial fibrillation
recurrence. J Cardiovasc Med (Hagerstown) 2006;7:29-38.
Copyright © 2009 Massachusetts Medical Society.

Risks of Long-Acting Beta-Agonists in Achieving Asthma Control
Jeffrey M. Drazen, M.D., and Paul M. O’Byrne, M.B.
In early December 2008, the Food and Drug Administration (FDA) held an unusual joint meeting
of the Pulmonary–Allergy Drugs Advisory Committee, the Drug Safety and Risk Management
Advisory Committee, and the Pediatric Advisory
Committee to consider the safety of long-acting
beta-agonists (LABAs). The meeting is described
in detail in a Perspective in this issue of the Journal by Kramer,1 who points out that decision making by the advisers and the FDA was hampered
by the lack of data about the safety of LABAs.
LABAs, which are administered by inhalation,
act by effecting prolonged stimulation of the β2adrenergic receptor. They were introduced into the
worldwide pulmonary market in the early 1990s
and approved for use in the United States in 1994.
As active pulmonary physicians, we can attest to
their effectiveness. In clinical trials2,3 and in individual encounters, most patients with asthma
who use these medications have improved lung
function, and many have diminished symptoms.
When LABAs are used together with inhaled corticosteroids, the combination reduces severe asthma exacerbations.3,4 No one is questioning whether these drugs provide therapeutic benefit.
However, since the introduction of LABAs there
has been a concern that they may be associated
with an enhanced risk of death from asthma. The
Salmeterol Multicenter Asthma Research Trial
(SMART), conducted to test the safety of the LABA
salmeterol, was stopped when an interim analysis
showed an enhanced risk of death for patients
taking salmeterol as compared with those taking
placebo.5 (In the trial, patients with asthma who
were not otherwise taking a LABA were randomly

assigned to a LABA or placebo for 28 weeks of
treatment while their usual asthma treatment was
continued.) The risk of death associated with salmeterol was about 1 in 700 patient-years of treatment.6 Many aspects of the design and conduct
of SMART have been criticized,7 but new clinical
trials to test the safety of LABAs have not been
launched.
At the meeting of the advisory committees, the
panels heard the available evidence concerning the
safety of LABAs. Unfortunately, very little new evidence on this issue has been accrued in the past
5 years. Despite the potential risks of these drugs,
the companies marketing them have not launched
trials powered to show their safety. There is widespread agreement that LABAs should never be
used as monotherapy for patients with asthma.
Current treatment guidelines actively discourage
this practice,8,9 and the FDA advisory committees
meeting in December came to a similar conclusion.1 Recent meta-analyses of all clinical trials
comparing the effects of combined treatment with
inhaled corticosteroids and LABAs with the use
of inhaled corticosteroids alone have shown a
small, nonsignificant increase in death from all
causes among the patients receiving the combined
treatment. Since these events were so infrequent,
the authors of these studies have argued that it
was not possible to establish or refute the role of
LABAs in causing them.10,11
In our opinion, because of confounding and
misclassification of death, this issue cannot be
resolved by epidemiologic studies or further debate: we need additional data. The onus lies with
the FDA and the makers of LABAs to design and

n engl j med 360;16  nejm.org  april 16, 2009

The New England Journal of Medicine
Downloaded from nejm.org on May 14, 2015. For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.

1671

 editorials

implement appropriately designed and powered
trials to determine the safety of these medications.
We recognize that these studies would need to
be very large and would be expensive, but as members of a community of physicians, we must demand that such studies be done, be done soon,
and be done correctly. To meet clinical equipoise,
the comparison should be between treatment with
inhaled corticosteroids alone and inhaled corticosteroids plus LABAs. The studies should also
include both pediatric and adult patients.
To date, the makers of these drugs have not
undertaken such large safety studies voluntarily;
the FDA may have to require it. Although these
studies will be expensive, given that the gross
sales of these drugs exceeded $6 billion in 2008,
even a trial costing $250 million would constitute about 2 weeks of gross profits. A pressing
need remains for data on the safety of LABAs, as
newer, even longer-acting LABAs are being developed to treat asthma. We urge the FDA to require
the start of adequately powered, well-designed
studies before the end of 2009, the completion of
enrollment in a year’s time, and the completion
of follow-up by the end of the second quarter of
2011. Until then, physicians should continue to
use LABAs to treat asthma, but only together with
inhaled corticosteroids. In particular, LABAs
should be used only in patients for whom other
controller medications alone do not provide adequate, rather than optimal, asthma control. We
know that LABAs are effective; the data must be
gathered to prove they are safe.
Dr. O’Byrne reports receiving consulting fees from AstraZeneca,
GlaxoSmithKline, Merck, Topigen, Resistentia, and Wyeth, lecture

1672

fees from AstraZeneca, GlaxoSmithKline, and Chiesi, and research
support from Alexion, AstraZeneca, Genentech, Medimmune,
Merck, Schering-Plough, and Wyeth. No other potential conflict
of interest relevant to this article was reported.
From the Department of Medicine, McMaster University, and
the Firestone Institute of Respiratory Health, St. Joseph’s Hospital (P.M.O) — both in Hamilton, ON, Canada.
1.  Kramer JM. Balancing the benefits and risks of inhaled

LABAs — the influence of values. N Engl J Med 2009;360:1592-5.
2.  Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with
symptoms on existing inhaled corticosteroid. Lancet 1994;
344:219-24.
3.  Bateman ED, Boushey HA, Bousquet J, et al. Can guidelinedefined asthma control be achieved? The Gaining Optimal
Asthma ControL study. Am J Respir Crit Care Med 2004;170:83644.
4.  Pauwels RA, Löfdahl CG, Postma DS, et al. Effect of inhaled
formoterol and budesonide on exacerbations of asthma. N Engl
J Med 1997;337:1405-11. [Erratum, N Engl J Med 1998;338:139.]
5.  Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM.
The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15-26. [Erratum, Chest
2006;129:1393.]
6.  Martinez FD. Safety of long-acting beta-agonists — an urgent need to clear the air. N Engl J Med 2005;353:2637-9.
7.  O’Byrne PM, Adelroth E. Beta2 déjà vu. Chest 2006;129:3-5.
8.  National Asthma Education and Prevention Program. Expert
Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma — summary report 2007. J Allergy Clin Immunol
2007;120:Suppl:S94-S138. [Erratum, J Allergy Clin Immunol 2008;
121:1330.]
9.  Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for
asthma management and prevention: GINA executive summary.
Eur Respir J 2008;31:143-78.
10.  Jaeschke R, O’Byrne PM, Mejza F, et al. The safety of longacting beta-agonists among patients with asthma using inhaled
corticosteroids: systematic review and metaanalysis. Am J Respir Crit Care Med 2008;178:1009-16.
11.  Sears MR, Ottosson A, Radner F, Suissa S. Long-acting betaagonists: a review of formoterol safety data from asthma clinical
trials. Eur Respir J 2009;33:21-32.
Copyright © 2009 Massachusetts Medical Society.

n engl j med 360;16  nejm.org  april 16, 2009

The New England Journal of Medicine
Downloaded from nejm.org on May 14, 2015. For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.