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editorial

T h e n e w e n g l a n d j o u r n a l o f medicine

Choice of Bronchodilator Therapy for Patients with COPDJadwiga A. Wedzicha, M.D.

Chronic obstructive pulmonary disease (COPD)

is a progressive airway inflammatory condition

that is associated with accelerated decline of lung

function and is characterized by worsening dys-

pnea with episodes of increased number and se-

verity of symptoms, termed exacerbations.1 Themain objectives of managing COPD are a reduc-

tion in the severity of symptoms and the preven-

tion of exacerbations.2 Bronchodilator therapy is

central to the management of COPD; this treat-

ment produces modest increases in lung function

as measured by spirometry and a reduction in

the dynamic hyperinf lation that leads to the dys-

pnea of COPD.3 Patients with COPD often pres-

ent to their physician with dyspnea, and broncho-

dilators are often the first therapy prescribed.

Initially, short-acting bronchodilators, such as al-

buterol, may be used, but in patients with persis-

tent symptoms, long-acting bronchodilators pro-

vide more uniform relief. Currently there are two

classes of long-acting bronchodilators available

long-acting 2-agonists and long-acting anti-

cholinergic agents, and both classes of agents, as

compared with placebo, have been shown to pro-

vide relief from symptoms in patients with COPD.

Although exacerbations are more common

with increasing severity of the disease, a substan-

tial number of patients, even those with moder-

ate COPD (defined as COPD in which the patientsforced expiratory volume in 1 second [FEV1] is

50% or more of the predicted value) are suscep-

tible to frequent exacerbations.4 Patients who

have frequent exacerbations are also likely to have

more symptoms, worse health status,5 faster dis-

ease progression,6 and an increased risk of death7;

therefore, it is important to make the diagnosis

of COPD in these patients accurately and to treat

them effectively. Subgroup analyses of recent large

COPD trials have shown that treatment with long-

acting 2-agonists or long-acting anticholiner-

gic agents, in addition to decreasing the fre-

quency of exacerbations in patients with severe

disease, also reduce exacerbations in patients

with moderate COPD.8,9

Since long-acting bronchodilators benefit thesepatients, it is important to ask which long-acting

bronchodilator should be the initial choice for

patients with COPD, especially those with mod-

erate disease. The National Institute for Health

and Clinical Excellence of England and Wales,

in its 2010 update of COPD treatment guidelines,

reviewed all studies that compared long-acting

2-agonists and long-acting anticholinergic agents

and came to the conclusion that there was no

evidence to favor one treatment over another.10

In this issue of the Journal, Vogelmeier and

colleagues report the results of a study that

makes some progress in addressing this impor-

tant question.11 The Prevention of Exacerbations

with Tiotropium in COPD trial (POET-COPD;

ClinicalTrials.gov number, NCT00563381), a large

international study, compared the effect of a long-

acting anticholinergic agent (tiotropium, at a dose

of 18 g once daily) with a long-acting 2-agonist

(salmeterol, at a dose of 50 g twice daily) over

the course of 1 year in 7376 patients with COPD

who had an FEV1

of 70% of the predicted value

or less. The focus of the study was the reductionof exacerbations, and the enrollment criteria in-

cluded a documented history of at least one ex-

acerbation in the previous year requiring therapy

or hospitalization. The primary end point was the

time to the first exacerbation, and secondary and

safety end points included other exacerbation

outcomes and serious adverse events, including

death. The results showed that, as compared with

salmeterol, tiotropium prolonged the time to the

first exacerbation, with a 17% reduction in the

The New England Journal of Medicine

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editorial

n engl j med 364;12 nejm.org march 24, 20111168

risk of an exacerbation. There was also a greater

reduction with tiotropium than with salmeterol

in the other exacerbation outcomes, such as the

annual number of moderate exacerbations (re-

quiring treatment with systemic glucocorticoids,

antibiotics, or both) and the annual number of

severe exacerbations (requiring hospitalization).

The incidence of serious adverse effects, includ-ing cardiovascular complications and deaths, was

similar between the two groups.

An important point to note about this trial

was that it was not a direct comparison of a long-

acting 2-agonist with a long-acting anticholin-

ergic agent, since concomitant medications were

allowed; more than 50% of the patients were re-

ceiving, on a regular basis, inhaled glucocorti-

coids that also reduce exacerbations.8 The fact

that the patients had had at least one treated

exacerbation in the previous year may explain the

high use of concomitant medications among thepatients in this trial. However, post hoc analyses

showed that the effect of tiotropium with respect

to the reduction in exacerbations was similar re-

gardless of the severity of the COPD and regard-

less of whether the patients were receiving in-

haled glucocorticoid therapy on a regular basis.

Large multicenter studies involving patients

with COPD are often difficult to perform, and

previous large trials have attempted to study a

wide range of outcomes. In contrast, the focus on

COPD exacerbations in the study by Vogelmeier

et al. enabled the data on exacerbations to be

carefully collected and validated. This trial thus

provides a good model for future COPD trials,

which should be focused on a specific and rele-

vant disease outcome. A strength of the study was

that the reporting of exacerbation outcomes was

detailed and was supplemented with daily diary

cards to confirm exacerbations and the intervals

between exacerbations, thus providing more ac-

curate event rates.

The main implications of this trial are for the

initial care of symptomatic patients with mod-erate disease and a history of recent exacerba-

tions. The trial evidence suggests that with respect

to exacerbation outcomes, tiotropium, adminis-

tered once daily, is superior to salmeterol, admin-

istered twice daily.11 However, novel, once-daily,

long-acting 2-agonists such as indacaterol are

now becoming available in Europe, and there is

some evidence that outcomes with indacaterol

are similar to those with tiotropium.12 There is

no evidence for the superiority of tiotropium in

patients with mild COPD (those in whom the

FEV1

is >70% of the predicted value) or sympto-

matic patients with moderate COPD but without

a history of exacerbations. However, in patients

with progressive COPD, combinations of inhaled

long-acting 2-agonists, long-acting anticholin-

ergic agents, glucocorticoids, and new antiin-flammatory agents such as oral phosphodiester-

ase-4 inhibitors may be indicated. Future trials

involving patients with COPD will need to study

which therapies and which specific combinations

are optimal for which COPD phenotypes and

disease severities, so that we can reduce the ad-

verse effects of this disabling disease.Disclosure forms provided by the author are available with the

full text of this article at NEJM.org.

From the Academic Unit of Respiratory Medicine, UniversityCollege London Medical School, University College London,

London.1. Wedzicha JA, Seemungal TAR. COPD exacerbations: defin-

ing their cause and prevent ion. Lancet 2007;370:786-96.

2. Global Initiative for Chronic Obstructive Lung Disease.

Global strategy for the diagnosis, management and prevention

of chronic obstructive pulmonary disease: 2009 update. (http://www.goldcopd.com.)

3. ODonnell DE, Revil l SM, Webb KA. Dynamic hyperinf lationand exercise intolerance in chronic obstructive pulmonary dis-

ease. Am J Respir Crit Care Med 2001;164:770-7.

4. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacer-bation in chronic obstructive pulmonary disease. N Engl J Med

2010;363:1128-38.

5. Seemungal TAR, Donaldson GC, Paul EA, Bestall JC, Jeffries

DJ, Wedzicha JA. Effect of exacerbation on quality of life in pa-

tients with chronic obstructive pulmonary disease. Am J RespirCrit Care Med 1998;157:1418-22.

6. Donaldson GC, Seemungal TAR, Bhowmik A, Wedzicha JA.The relationship between exacerbat ion frequency and lung func-

tion decline in chronic obstructive pulmonary disease. Thorax2002;57:847-52. [Erratum, Thorax 2008;63:753.]

7. Soler-Catalua JJ, Martnez-Garca MA, Romn Snchez P,

Salcedo E, Navarro M, Ochando R. Severe acute exacerbationsand mortality in patients with chronic obstructive pulmonary

disease. Thorax 2005;60:925-31.

8. Jenkins CR, Jones PW, Calverley PM, et al. Efficacy of salmet-

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tive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir Res 2009;10:59.

9. Decramer M, Celli B, Kesten S, Lystig T, Mehra S, TashkinDP. Effect of tiotropium on outcomes in patients with moderate

chronic obstructive pulmonary disease (UPLIFT): a prespecifiedsubgroup analysis of a randomised controlled trial. Lancet2009;374:1171-8.

10. CG101 chronic obstructive pulmonary disease (update): fullguideline. London: National Institute for Health and Clinical

Excellence, 2010. (http://guidance.nice.org.uk/CG101/Guidance.)

11. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus

salmeterol for the prevention of exacerbations of COPD. N Engl

J Med 2011;364:1093-103.

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dilators for chronic obstructive pulmonary disease: indacaterolversus tiotropium. Am J Respir Crit Care Med 2010;182:155-62.

Copyright 2011 Massachusetts Medical Society.

The New England Journal of Medicine

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Copyright 2011 Massachusetts Medical Society. All rights reserved.