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Budesonide plus formoterol for reliever therapy in asthma
Comment
Budesonide plus formoterol for reliever therapy in asthma
www.thelancet.com Vol 368 August 26, 2006
as-needed components in the budesonide-formoterol combination inhaler. It did not include an arm with guideline-recommended therapy (increase in daily dose of combination therapy). Therefore clinical generalisation of the results would be inappropriate. Even if as-needed treatment with the combination product improved most outcomes, no effects were seen on two important ones: percentage asthma-control days and patients’ quality of life. Moreover, the patients on as-needed combination treatment still woke up on average once every week because of asthma, on 60% of the days the asthma was not controlled, and on 16% of days the patients had mild exacerbation days. Although better than baseline, this is not good asthma control.1,2 Even if direct comparisons should be made with caution, the level of daily asthma control seemed much poorer than the level reported in a recent study assessing the recommendations of the guidelines.7 This finding might not be surprising, considering that the strategy in Rabe and colleague’s study requires a certain degree of uncontrolled asthma before the patient takes enough extra as-needed treatment to actually make a difference to daily asthma control. Could it be that the effect of as-needed combination treatment is greater on asthma exacerbation rate than on daily asthma control? The findings of Rabe and colleagues’ study and other studies3 suggest so. In Rabe’s study, large reductions were seen in the occurrence of exacerbations to 19/100 patient-years. This is quite similar to the 14 and 27/100 patient years reported in strata 2 and 3, respectively, of the GOAL study, which assessed guideline
See Articles page 744
We do not have the rights to reproduce this image on the web. Photolibrary.com
The recommended treatment for asthma is maintenance therapy with inhaled corticosteroids or combination therapy with an inhaled corticosteroid and a long-acting β2 agonist.1,2 Furthermore, treatment with a rapid-acting β2 agonist is used as rescue therapy.1,2 When the asthma is not controlled, the level of maintenance therapy should be increased. This strategy has recently been challenged by studies that suggest the use of an inhaled corticosteroid and a long-acting β2 agonist in one inhaler for both maintenance and as-needed therapy.3 Because this option necessarily increases the use of two different drugs, the question has been raised as to their relative contribution to the additional clinical effects. In today’s Lancet, Klaus Rabe and colleagues4 report the findings of a study designed to address that question by comparing the effects of as-needed treatment with terbutaline, formoterol, and the combination of formoterol and budesonide in one inhaler on daily asthma control and the occurrence of asthma exacerbations in patients whose asthma is not controlled on treatment with a formoterol/budesonide 4·5/160 μg combination twice daily. The conclusions were clear for one of the components: as-needed formoterol alone had no significant effect on daily asthma control, mild exacerbations, or admissions to hospital and emergency-room visits. So, simply changing from a short-acting β2 agonist to formoterol for as-needed use in patients with uncontrolled asthma is not a good option. The conclusions for as-needed combination treatment were less clear. Although the interpretation of the data would have been clearer if the study had included an as-needed budesonide arm, the findings strongly support the idea that patients with uncontrolled asthma should have their dose of inhaled corticosteroid increased. This suggestion is in agreement with the findings from other studies and also from studies that increased the dosing frequency of inhaled corticosteroids in patients with uncontrolled asthma.5–7 As-needed treatment with a combination product is a new approach to managing uncontrolled asthma. However, it would be an inappropriate over-simplification to claim that the findings in Rabe and colleague’s study challenge the recommendations of the guidelines. Their study was designed to address one research question only, the relative contribution of the two
707
Comment
treatment recommendations in a comparable group of patients.7 However, the proportion of exacerbations leading to an emergency room visit or hospitalisation in Rabe’s study (70/194 exacerbations) is higher than the proportion in the GOAL study (17/146 exacerbations in stratum 3). More studies are needed to assess this potential difference in the severity of exacerbations between the novel and guideline-recommended treatment approaches. Finally, the findings in Rabe’s study were in patients with severe uncontrolled asthma on a low dose of combination treatment. This group is a small proportion of the whole asthma population. Most patients with asthma can achieve guideline-defined asthma control when treated according to the recommendations.7–9 Therefore generalising the findings to the whole asthma population seems inappropriate at present. Søren Pedersen Paediatric Research Unit, Kolding Hospital, K 6000 Kolding, Denmark [email protected]
I have received research funding, consultancies, and speakers’ fees from Altana, AstraZeneca, GlaxoSmithKline, Merck. 1
2
3
4
5
6
7
8
9
Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention: NHLBI/WHO workshop report, publication no. 02–3659. 2002: http://www.ginasthma.com/Guidelineitem. asp??l1=2&l2=1&intId=60 (accessed Aug 15, 2006). British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax 2003; 58 (suppl 1): i1–i94. O’Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005; 171: 129–36. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet 2006; 368: 744–53. Pauwels RA, Lofdahl CG, Postma DS, for the Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997; 337: 1405–11. Toogood JH, Baskerville J, Jennings B, Lefcoe NM, Johansson S. Influence of dosing frequency and schedule on the response of chronic asthmatics to the aerosol steroid, budesonide. J Allergy Clin Immunol 1982; 70: 288–98. Bateman ED, Boushey HA, Bousquet J, GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004; 170: 836–44. O’Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001; 164: 1392–97. Pauwels RA, Pedersen S, Busse WW, on behalf of the START Investigator Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003; 361: 1071–76.
Inhaled corticosteroids and asthma prevention See Perspectives page 725 See Articles page 754
708
In today’s Lancet, Clare Murray and colleagues1 report a trial that tested the hypothesis that inhaled corticosteroids, when administered to symptomatic preschool children, can change the natural course of asthma. There was no difference between drug and placebo. Two other similar trials (PEAK and PAC), which failed to show a difference, were recently published.2,3 It is useful first to define what is meant by the natural course of asthma. There ought to be a first period during which there is no clinical evidence of the disease, and during this phase factors that determine inception are at work. At inception, which could be identified with the first manifestations of the disease, two scenarios are possible: either the physiological and anatomical features, congenital or acquired, that underlie the subsequent chronic expression of the disease are already present (course A–C, figure), or they are not (B–D), and develop concomitantly with the transition between initial phase and full-blown chronic illness. Remission (B–E) is also possible and is common in young children, the so-called transient wheezers.4
The three trials (and a previous one, also negative, in schoolchildren5) based their rationale on the results of several longitudinal studies of asthma. These studies showed that a high proportion of cases of persistent asthma start in early life.6 Patients with persistent asthma have diminished spirometric levels of lung function7 and there is an inverse correlation between these levels and severity and persistence of the disease.8 These lung function abnormalities are already established by the early school years and do not usually progress much further thereafter.9 In infants tested shortly after birth, those who subsequently developed asthma have lung function levels that are not significantly lower than those of their peers.10 Studies of airway biopsy specimens from symptomatic children at different ages have shown that the characteristic anatomical features of chronic adult asthma (airway remodelling) are rarely seen in wheezy preschoolers, but are consistently found in older children with asthma.11 Thus it seemed reasonable to conclude that the asthmatic lung is most often acquired during the preschool years (B–D, figure), and that aggressively www.thelancet.com Vol 368 August 26, 2006
Budesonide plus formoterol for reliever therapy in asthma
www.thelancet.com Vol 368 August 26, 2006
as-needed components in the budesonide-formoterol combination inhaler. It did not include an arm with guideline-recommended therapy (increase in daily dose of combination therapy). Therefore clinical generalisation of the results would be inappropriate. Even if as-needed treatment with the combination product improved most outcomes, no effects were seen on two important ones: percentage asthma-control days and patients’ quality of life. Moreover, the patients on as-needed combination treatment still woke up on average once every week because of asthma, on 60% of the days the asthma was not controlled, and on 16% of days the patients had mild exacerbation days. Although better than baseline, this is not good asthma control.1,2 Even if direct comparisons should be made with caution, the level of daily asthma control seemed much poorer than the level reported in a recent study assessing the recommendations of the guidelines.7 This finding might not be surprising, considering that the strategy in Rabe and colleague’s study requires a certain degree of uncontrolled asthma before the patient takes enough extra as-needed treatment to actually make a difference to daily asthma control. Could it be that the effect of as-needed combination treatment is greater on asthma exacerbation rate than on daily asthma control? The findings of Rabe and colleagues’ study and other studies3 suggest so. In Rabe’s study, large reductions were seen in the occurrence of exacerbations to 19/100 patient-years. This is quite similar to the 14 and 27/100 patient years reported in strata 2 and 3, respectively, of the GOAL study, which assessed guideline
See Articles page 744
We do not have the rights to reproduce this image on the web. Photolibrary.com
The recommended treatment for asthma is maintenance therapy with inhaled corticosteroids or combination therapy with an inhaled corticosteroid and a long-acting β2 agonist.1,2 Furthermore, treatment with a rapid-acting β2 agonist is used as rescue therapy.1,2 When the asthma is not controlled, the level of maintenance therapy should be increased. This strategy has recently been challenged by studies that suggest the use of an inhaled corticosteroid and a long-acting β2 agonist in one inhaler for both maintenance and as-needed therapy.3 Because this option necessarily increases the use of two different drugs, the question has been raised as to their relative contribution to the additional clinical effects. In today’s Lancet, Klaus Rabe and colleagues4 report the findings of a study designed to address that question by comparing the effects of as-needed treatment with terbutaline, formoterol, and the combination of formoterol and budesonide in one inhaler on daily asthma control and the occurrence of asthma exacerbations in patients whose asthma is not controlled on treatment with a formoterol/budesonide 4·5/160 μg combination twice daily. The conclusions were clear for one of the components: as-needed formoterol alone had no significant effect on daily asthma control, mild exacerbations, or admissions to hospital and emergency-room visits. So, simply changing from a short-acting β2 agonist to formoterol for as-needed use in patients with uncontrolled asthma is not a good option. The conclusions for as-needed combination treatment were less clear. Although the interpretation of the data would have been clearer if the study had included an as-needed budesonide arm, the findings strongly support the idea that patients with uncontrolled asthma should have their dose of inhaled corticosteroid increased. This suggestion is in agreement with the findings from other studies and also from studies that increased the dosing frequency of inhaled corticosteroids in patients with uncontrolled asthma.5–7 As-needed treatment with a combination product is a new approach to managing uncontrolled asthma. However, it would be an inappropriate over-simplification to claim that the findings in Rabe and colleague’s study challenge the recommendations of the guidelines. Their study was designed to address one research question only, the relative contribution of the two
707
Comment
treatment recommendations in a comparable group of patients.7 However, the proportion of exacerbations leading to an emergency room visit or hospitalisation in Rabe’s study (70/194 exacerbations) is higher than the proportion in the GOAL study (17/146 exacerbations in stratum 3). More studies are needed to assess this potential difference in the severity of exacerbations between the novel and guideline-recommended treatment approaches. Finally, the findings in Rabe’s study were in patients with severe uncontrolled asthma on a low dose of combination treatment. This group is a small proportion of the whole asthma population. Most patients with asthma can achieve guideline-defined asthma control when treated according to the recommendations.7–9 Therefore generalising the findings to the whole asthma population seems inappropriate at present. Søren Pedersen Paediatric Research Unit, Kolding Hospital, K 6000 Kolding, Denmark [email protected]
I have received research funding, consultancies, and speakers’ fees from Altana, AstraZeneca, GlaxoSmithKline, Merck. 1
2
3
4
5
6
7
8
9
Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention: NHLBI/WHO workshop report, publication no. 02–3659. 2002: http://www.ginasthma.com/Guidelineitem. asp??l1=2&l2=1&intId=60 (accessed Aug 15, 2006). British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax 2003; 58 (suppl 1): i1–i94. O’Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005; 171: 129–36. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet 2006; 368: 744–53. Pauwels RA, Lofdahl CG, Postma DS, for the Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997; 337: 1405–11. Toogood JH, Baskerville J, Jennings B, Lefcoe NM, Johansson S. Influence of dosing frequency and schedule on the response of chronic asthmatics to the aerosol steroid, budesonide. J Allergy Clin Immunol 1982; 70: 288–98. Bateman ED, Boushey HA, Bousquet J, GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004; 170: 836–44. O’Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001; 164: 1392–97. Pauwels RA, Pedersen S, Busse WW, on behalf of the START Investigator Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003; 361: 1071–76.
Inhaled corticosteroids and asthma prevention See Perspectives page 725 See Articles page 754
708
In today’s Lancet, Clare Murray and colleagues1 report a trial that tested the hypothesis that inhaled corticosteroids, when administered to symptomatic preschool children, can change the natural course of asthma. There was no difference between drug and placebo. Two other similar trials (PEAK and PAC), which failed to show a difference, were recently published.2,3 It is useful first to define what is meant by the natural course of asthma. There ought to be a first period during which there is no clinical evidence of the disease, and during this phase factors that determine inception are at work. At inception, which could be identified with the first manifestations of the disease, two scenarios are possible: either the physiological and anatomical features, congenital or acquired, that underlie the subsequent chronic expression of the disease are already present (course A–C, figure), or they are not (B–D), and develop concomitantly with the transition between initial phase and full-blown chronic illness. Remission (B–E) is also possible and is common in young children, the so-called transient wheezers.4
The three trials (and a previous one, also negative, in schoolchildren5) based their rationale on the results of several longitudinal studies of asthma. These studies showed that a high proportion of cases of persistent asthma start in early life.6 Patients with persistent asthma have diminished spirometric levels of lung function7 and there is an inverse correlation between these levels and severity and persistence of the disease.8 These lung function abnormalities are already established by the early school years and do not usually progress much further thereafter.9 In infants tested shortly after birth, those who subsequently developed asthma have lung function levels that are not significantly lower than those of their peers.10 Studies of airway biopsy specimens from symptomatic children at different ages have shown that the characteristic anatomical features of chronic adult asthma (airway remodelling) are rarely seen in wheezy preschoolers, but are consistently found in older children with asthma.11 Thus it seemed reasonable to conclude that the asthmatic lung is most often acquired during the preschool years (B–D, figure), and that aggressively www.thelancet.com Vol 368 August 26, 2006