Editorial
Step-up therapy in uncontrolled asthma: Choices and outcomes Malcolm R. Sears, MB, FRACP, FRCPC, FAAAAI
Hamilton, Ontario, Canada
Key words: Asthma, inhaled corticosteroids, long-acting b-agonist
Guidelines for the management of mild to moderate persistent asthma that remains suboptimally controlled despite use of an inhaled corticosteroid (ICS) indicate 2 step-up options: adding a long-acting b-agonist (LABA) to an existing ICS, or increasing the dose of ICS.1 Randomized controlled clinical trials have shown that both currently available LABAs, formoterol and salmeterol, when added to ICS, improve symptom control and lung function, and reduce exacerbations compared with higher doses of ICS alone.2,3 Combinations of ICS with LABA in a single inhaler have become widely used as regular maintenance therapy in asthma. More recently, ICS combined with formoterol, which is both rapid-acting and long-acting, has been used for both maintenance and reliever therapy with improvement in control despite significant reduction in total ICS exposure.4 New ultra-long-acting b-agonists are now in clinical trials,5 and combinations of these agents with once-daily ICS are expected to become available. What do we know about the relative merits of adding LABA versus increasing ICS in real life? Clinical trial data may not reflect outcomes in everyday practice. Adherence to therapy, concomitant smoking, respiratory and other comorbidities, and treatment preferences of physicians affect real-world situations. Analysis of long-term outcomes of these strategies in large populations should provide useful information to supplement data from randomized controlled trials. Such real-life outcomes are reported by Thomas et al6 in this issue. Using the United Kingdom General Practice Research Database, the authors assessed outcomes in 64,348 patients with asthma for 12 months after their baseline treatment with ICS monotherapy was changed by the addition of a LABA, or by an increase in the dose of ICS. After adjusting for baseline differences and for confounders including sex, body mass index, socioeconomic status, comorbidities, smoking, year of step-up, short-acting b-agonist (SABA) use, and other medications, the authors came to a somewhat paradoxical conclusion. On the one hand, they reported that the group in whom ICS was increased
From McMaster University, Firestone Institute for Respiratory Health, St Joseph’s Healthcare Hamilton. Disclosure of potential conflict of interest: M. R. Sears has served as a consultant and speaker for AstraZeneca, Merck Frosst, and Nycomed and holds a Chair in Respiratory Epidemiology jointly endowed by AstraZeneca and McMaster University. Received for publication October 24, 2008; accepted for publication October 27, 2008. Reprint requests: Malcolm R. Sears, MB, FRACP, FRCPC, FAAAAI, Professor of Medicine, McMaster University, Firestone Institute for Respiratory Health, St Joseph’s Healthcare Hamilton, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada. E-mail:
[email protected]. J Allergy Clin Immunol 2009;123:122-3. 0091-6749/$36.00 Ó 2009 American Academy of Allergy, Asthma & Immunology doi:10.1016/j.jaci.2008.10.045
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had a lower likelihood of achieving ‘‘successful treatment’’ (defined as no hospitalizations, no oral corticosteroid use, and average SABA use <1 dose/day) compared with those with addition of LABA (odds ratio [OR], 0.75; 95% CI, 0.72-0.79). On the other hand, these same patients with increased ICS were less likely to need oral corticosteroids (adjusted OR, 0.75; 95% CI, 0.710.79), especially 3 or more courses (adjusted OR, 0.50; 95% CI, 0.46-0.55) and had fewer hospitalizations (adjusted OR, 0.69; 95% CI, 0.59-0.81), all of which reflect better control. These findings appear contradictory: how can a strategy be less successful, yet result in fewer exacerbations and hospitalizations? Which strategy in fact provides better asthma control? Although there were baseline differences between the LABA and increased ICS groups (the LABA group was older, more likely to be female, more likely to have cardiac disease, used more SABA and more oral corticosteroid), these factors do not explain the paradox. In unadjusted analyses, the LABA cohort had a higher proportion of unsuccessful treatment, but adjustment for these confounders resulted in a higher proportion of individuals with successful treatment. Nor did stratification by age or the use of oral corticosteroid in the year before step-up substantially alter the findings. Rather, the explanation of the paradox appears to lie in the criteria for defining ‘‘successful treatment.’’ Of the 3 components of the authors’ definition of ‘‘successful treatment,’’ hospitalizations and short courses of oral corticosteroid were infrequent in the ICS group, but there was a greater use of SABA (OR for needing any SABA in the 12 months after step-up was 1.67; 95%, CI 1.59-1.76). The more frequent need for SABA as relief medication >1/day resulted in the ICS cohort having a lower likelihood of ‘‘successful treatment.’’ Is this conclusion legitimate? In 1981, Shepherd et al7 reported a small yet highly influential study of regular versus as-needed use of the SABA albuterol. In a short crossover trial, 18 patients received albuterol 200 mg or matching placebo 4 times daily for a week. During regular albuterol treatment, fewer rescue doses of albuterol were used (2.9 vs 5.7 puffs/day), and evening and bedtime peak expiratory flow measurements were 20 L/min higher than in the placebo week. Ignoring the fact that the total daily dose of albuterol was actually substantially higher (7.9 puffs/day of regular treatment added to 2.9 as-needed puffs gives a total of 10.8 puffs/day vs 5.7 in the as-needed albuterol group) and that the improved peak flow rates were measured shortly after use of albuterol, regular b-agonist therapy was deemed to provide better asthma control and was widely promoted. Similar issues of counting puffs of b-agonist arise in the current report.6 Subjects in the LABA group used fewer doses of rescue SABA and therefore were more often able to achieve the authors’ definition of ‘‘successful treatment’’—but the total dose of b-agonist (ie, including the LABA used regularly each day) is not considered in this definition. Counting puffs of rescue b-agonist may not be an appropriate outcome measure when regular b-agonist
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use is an integral part of the treatment strategy. This report again raises the question of how asthma control should be judged when LABA is included in the treatment regimen. Does less use of SABA make the addition of LABA the preferred strategy? The safety of LABAs in asthma has been much debated, because postmarketing trials in the United Kingdom and the United States suggested an increased risk of exacerbations and deaths with use of salmeterol.8,9 Use of ICS was not mandatory in those studies, and post hoc analyses suggest the lack of ICS likely contributed to these adverse outcomes, especially in the US study.9 One putative benefit of adding LABA to baseline ICS is the ability to reduce the dose of ICS (the steroid-sparing effect) while maintaining asthma control. However, the potential for LABA to control symptoms and maintain lung function despite increasing eosinophilic inflammation when ICS dose is inadequate (masking) has been clearly demonstrated.10 In a study of patients using combined ICS and LABA therapy, ICS could not be totally withdrawn without loss of asthma control.11 In another study, halving the dose of ICS while using concomitant LABA was associated with a (nonsignificant) doubling of the risk of exacerbation, and full withdrawal of ICS with a highly significant 4-fold increased risk of treatment failure.12 There are ample data indicating that patients with asthma must maintain adequate ICS in their treatment regimen for good asthma control. The fact that the group given an increased dose of ICS in the report of Thomas et al6 had fewer hospitalizations and fewer courses of oral corticosteroids strongly suggests better overall control of airway inflammation with increased ICS compared with the LABA group, and suggests that the dose of ICS in those given LABA was insufficient. Despite the greater need for rescue SABA <1/day, the group with increased ICS used less b-agonist in total compared with those in the LABA add-on group, and is achieving greater control as judged by the outcomes of hospitalizations and need for oral corticosteroids. The findings in this report underscore the importance of maintaining adequate ICS dosing in patients using LABA therapy. In the pivotal study by Pauwels et al,2 the greatest reduction in exacerbations occurred in patients receiving both a higher dose of ICS and the addition of a LABA. Combination ICS/LABA therapy is convenient and effective, but a sufficient ICS dose is required for maximum benefit and safety. Adequacy of ICS therapy can be objectively assessed in specialist practices in which measurement of sputum eosinophils,13 airway responsiveness,14 or exhaled nitric measurements15 are available to guide therapy, but the majority of physicians must make judgments regarding ICS dose on clinical grounds. For many patients, addition of a LABA to ICS has been remarkably effective in improving
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symptom control, lung function, and quality of life. However, exacerbations and loss of asthma control in patients using combination therapy should strongly suggest the need to increase the dose of ICS rather than rely on the long-acting bronchodilator. Should LABA be added to ICS? Yes, provided the dose of ICS is sufficient to control the underlying inflammatory processes. REFERENCES 1. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 2008;31:143-78. 2. Pauwels RA, Lofdahl C-G, Postma DS, Tattersfield AE, O’Byrne P, Barnes PJ, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997;337:1405-11. 3. Greening AP, Ind PW, Northfield M, Shaw G. Allen & Hanburys Limited UK Study Group. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994;344:219-24. 4. Buhl R, Vogelmeier C. Budesonide/formoterol maintenance and reliever therapy: a new treatment approach for adult patients with asthma. Curr Med Res Opin 2007; 23:1867-78. 5. Beeh KM, Derom E, Kanniess F, Cameron R, Higgins M, van As A. Indacaterol, a novel inhaled b2-agonist, provides sustained 24-h bronchodilation in asthma. Eur Respir J 2007;29:871-8. 6. Thomas M, von Ziegenweidt J, Lee AJ, Price D. High-dose inhaled corticosteroids versus add-on long acting beta agonists in asthma: an observational study. J Allergy Clin Immunol 2009;123:116-21. 7. Shepherd GL, Hetzel MR, Clark TJH. Regular versus symptomatic aerosol bronchodilator treatment of asthma. Br J Dis Chest 1981;75:215-7. 8. Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993;306:1034-7. 9. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15-26. 10. McIvor RA, Pizzichini E, Turner MO, Hussack P, Hargreave FE, Sears MR. Potential masking effects of salmeterol on airway inflammation in asthma. Am J Respir Crit Care Med 1998;158:924-30. 11. Lazarus SC, Boushey HA, Fahy JV, Chinchilli VM, Lemanske RF, Sorkness CA, et al. Long-acting b2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA 2001;285:2583-93. 12. Lemanske RF, Sorkness CA, Mauger EA, Lazarus SC, Boushey HA, Fahy JV, et al. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. JAMA 2001;285:2594-603. 13. Jayaram L, Pizzichini MM, Cook RJ, Boulet L-P, Lemiere C, Pizzichini E, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J 2006;27:483-94. 14. Sont JK, Willems LNA, Bel EH, Han J, van Krieken JM, Vanderbroucke JP, et al. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. Am J Respir Crit Care Med 1999;159:1043-51. 15. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005;352: 2163-73.