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Spoilt for Choice?

London Chest Hospital, Barts and The London NHS Trust, London, United Kingdom

Current guidelines on the management of asthma recommend that all those except patients with mild intermittent disease should take regular therapy with antiinflammatory properties (1, 2). All guidelines advocate inhaled corticosteroids as the first choice. The question sometimes arises: "What should be done in patients who cannot or will not take inhaled corticosteroids?" Chromones have trivial beneficial effect and are inconvenient, requiring dosing four times a day. It has been suggested that a leukotriene receptor antagonist, the combination of leukotriene receptor antagonist and a long-acting ₂ agonist, or low-dose theophyllines may provide an alternative at this step. The articles by Deykin and coworkers (pp. 228–234) and The American Lung Association Asthma Clinical Research Centers (pp. 235–242) in this issue of the Journal provide some helpful data in this regard (3, 4).

Daykin and coworkers compared, in a crossover design study, montelukast plus salmeterol with low-dose inhaled steroids and salmeterol. The combination of low-dose inhaled steroid and salmeterol out-performed the alternative option in terms of pulmonary function, rescue ₂ agonist use, quality of life, exacerbation rates, and measures of airway inflammation. Although there is no placebo group, the changes in the montelukast and salmeterol group show little absolute evidence of efficacy. The trial reported by Irvin and colleagues investigated the addition of montelukast or low-dose theophylline to patients with poorly controlled asthma. Most of the patients included were taking inhaled corticosteroids, but there was a sub-group who were not. Despite the evidence from randomized controlled trials of the efficacy of montelukast (5, 6) in this group of patients, theophylline proved superior in terms of asthma control.

What do these studies tell us about controller therapy at step 2? First, they do nothing to supplant the recommendation for low-dose inhaled corticosteroids, as they demonstrate that the combination of montelukast plus salmeterol or montelukast alone provides little benefit even though there is some weak activity for oral theophyllines. Practitioners should therefore do everything in their power to persuade patients to take inhaled corticosteroids, as any other option will be markedly inferior.

The second area in which these trials help us is in the decision about additional therapy in patients not controlled on low-dose inhaled corticosteroids. Currently, guidelines recommend the addition of long-acting ₂ agonists—though with recent concerns, right or wrong, about the safety of long-acting ₂ agonists, some have advocated alternative strategies (7, 8). The trial by Irvin and coworkers shows that the addition of low-dose oral theophylline or montelukast led to no improvement in asthma control, although both produced a minor improvement in FEV₁. Thus two of the alternative strategies which have been advocated have been shown to have very little effect. What should physicians do when confronted with the problem of a patient on low-dose inhaled corticosteroids but not adequately controlled? First, although trials have shown a beneficial effect with the addition of long-acting ₂ agonists to low doses of inhaled corticosteroids, it needs to be borne in mind that reversibility to a bronchodilator is often an entry criterion to these studies, therefore making it likely that a long-acting ₂ agonist will do well. Second, patients with unstable asthma and recent exacerbations are usually excluded; it is in this group with their proven ability to reduce asthma exacerbations that inhaled corticosteroids are particularly helpful. Lastly, smokers and ex-smokers are often excluded from these types of trials, but we now have evidence that smokers and ex-smokers require higher doses of inhaled corticosteroids (9, 10). The first measure should be to optimize inhaled corticosteroid dosing before adding in a new treatment. If, despite this, asthma control is inadequate, then the best therapeutic option is to add a long-acting ₂ agonist. It is important to review, after a suitable period of time, whether the additional therapy has been beneficial (2).

There are some other additional messages that these two trials provide. First, they demonstrate how important it is that clinical trials of drug therapy are not just performed by the pharmaceutical industry. Governments need to understand that these expensive trials have to be funded. Poor compliance and adherence are undoubtedly barriers to good asthma treatment. It has been suggested, though with very little support, that compliance with oral therapies is superior to that with inhaled. Irvin and colleagues are to be applauded for making measures of compliance using plasma drug levels; these showed that by the end of 24 wk, adherence had fallen to only 60% in both groups despite the fact that their asthma was not well controlled. Finally, the studies demonstrate how, for evidence-based clinical practice, the randomized controlled trial in appropriately chosen populations remains the gold standard. Following the renewed concerns about the safety of long-acting ₂ agonists, various authorities have advocated adding theophyllines, adding leukotriene antagonists, and even adding long acting anti-muscarinic agents to low-dose inhaled steroids largely on the basis of either very small studies or arguments about additional antiinflammatory benefits (7, 8). These two studies show the flaws in these arguments.

FOOTNOTES

Conflict of Interest Statement: NCB has lectured for and had consultancy arrangements with GlaxoSmithKline (GSK). For GSK consultancies, he received $8,000 in 2003 and 2004. For lectures, $15,000 in 2003, £20,000 in 2004, and $25,000 in 2005. For GSK Advisory boards he received $4,500 in 2003, $4,500 in 2004, and $4,500 in 2005. For Altana advisory boards he received $3,000 in 2004 and $3,000 in 2005. He has received research funding by GSK for which he received $300,000 in 2003, by AstraZeneca, $40,000 in 2005.

REFERENCES

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3. Deykin A, Wechsler ME, Boushey HA, Chinchilli VM, Kunselman SJ, Craig TJ, DiMango E, Fahy JV, Kraft M, Leone F, et al. Combination therapy with a long-acting -agonist and a leukotriene antagonist in moderate asthma. Am J Respir Crit Care Med 2007;175:228–234.[Abstract/Free Full Text]
4. The American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. Am J Respir Crit Care Med 2007;175:235–242.[Abstract/Free Full Text]
5. Laviolette M, Malstrom K, Lu S, Chernivinsky P, Pujer J-C, Peszek I, Zhang JI, Reiss TF. Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med 1999;160:1862–1868.[Abstract/Free Full Text]
6. Malstrom K, Rodriguez-Gomez J, Guerra C, Villaran A, Pineiro LX, Wei B, Seidenberg C, Reiss TF. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma: a randomized, controlled trial. Montelukast/Beclomethasone Study Group. Ann Intern Med 1999;130:487–495.[Abstract/Free Full Text]
7. Martinez FD. Safety of long-acting beta agonists – an urgent need to clear the air. N Engl J Med 2005;353:2637–2639.[Free Full Text]
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Related articles in AJRCCM:

Combination Therapy with a Long-Acting -Agonist and a Leukotriene Antagonist in Moderate Asthma

Aaron Deykin, Michael E. Wechsler, Homer A. Boushey, Vernon M. Chinchilli, Susan J. Kunselman, Timothy J. Craig, Emily DiMango, John V. Fahy, Monica Kraft, Frank Leone, Stephen C. Lazarus, Robert F. Lemanske, Jr., Richard J. Martin, Gene R. Pesola, Stephen P. Peters, Christine A. Sorkness, Stanley J. Szefler, Elliot Israel, and for the National Heart, Lung, and Blood Institute's Asthma Clinical Research Network
AJRCCM 2007 175: 228-234. [Abstract] [Full Text]  

Clinical Trial of Low-Dose Theophylline and Montelukast in Patients with Poorly Controlled Asthma

The American Lung Association Asthma Clinical Research Centers
AJRCCM 2007 175: 235-242. [Abstract] [Full Text]  

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