The Best Step-up Regimen for Uncontrolled Asthma in Children
Lemanske RF, Mauger DT, Sorkness CA, et al, for the Childhood Asthma Research and Education (CARE) Network of the National, Heart, Lung, and Blood Institute.
N Engl J Med. 2010;362:975-985.
Lemanske and colleagues reviewed data demonstrating that children in a clinical trial of inhaled corticosteroid (ICS) for asthma may still have periods of poor control, so some type of step-up controller therapy is often needed. Few studies have been conducted in children to guide clinicians in the selection of the step-up therapy that best controls asthma after first-line ICS.
This study evaluated whether any of 3 regimens for step-up controller therapy were better in children with inadequately controlled asthma. The 3 regimens were increased ICS dose, adding a long-acting beta-agonist (LABA), or adding a leukotriene-receptor antagonist (LTRA). Participants were children 6-17 years of age with mild-to-moderate asthma, all of whom met the prespecified criteria for this classification based on National Heart, Lung, and Blood Institute guidelines.
All children participated in an 8-week run-in trial, during which they took 100 µg of inhaled fluticasone per day. If that regimen did not control the asthma, the child began the 48-week comparative trial. During the 48 weeks, each child spent 16 weeks on each of the 3 regimens. During ICS step-up periods, they received 250 µg of inhaled fluticasone per day; during the LABA step-up periods, they received 100 µg of inhaled fluticasone plus 50 µg of salmeterol per day; finally, during the LTRA step-up periods, the children received 100 µg of inhaled fluticasone plus 5-10 mg of montelukast per day. The children took dummy/placebo preparations of inactive drug, plus the active drug, during each 16-week period for purposes of masking. To allow for washout when switching regimens, the investigators analyzed the last 12 weeks of each cycle to determine the degree of asthma control attributable to each regimen.
Children were allowed oral prednisone treatment for exacerbations of asthma, and they were seen routinely every 4 weeks for symptom monitoring. The investigators also measured quality of life. The goal of the study was to determine which regimen performed better as evidenced by use of oral or systemic corticosteroids; number of "asthma control days" (eg., no use of rescue medication or symptoms and peak flow variation < 20%); and higher forced expiratory volume in 1 second (FEV1). A regimen was considered better than another if, while on that regimen, the child took at least 180 mg less systemic corticosteroids, experienced an increase in asthma control of at least 31 days in the 12 weeks, or if FEV1 was at least 5% higher than on another regimen, in that order of importance. For example, if someone met the definition of "improved" by receiving less steroids, then asthma control days and FEV1 measurements were ignored. In that manner, each child’s degree of asthma control was compared with that during the other cycles.
Four hundred eighty patients were enrolled in the study. Of those, asthma was uncontrolled in 182 during the run-in period, and therefore they were eligible for the full trial. Of these 182 children, 157 (86%) completed the full trial and 165 completed at least 2 treatment cycles. Ninety-eight percent of the patients did better on at least 1 of the step-up regimens than on the other regimens. Overall, LABA was best for more patients. When comparing LABA with LTRA, 52% of children responded better to LABA and 34% responded better to LTRA. In a similar fashion, when LABA was compared with ICS, 54% of children experienced a better response on LABA compared with 32% who did better on LTRA. Performance of ICS and LTRA was almost equal.
Many factors were not predictive of a child experiencing a differential response, including degree of response to methacholine challenge, fraction of exhaled nitric oxide, or genetic markers. Children with better baseline control of asthma at study entry were more likely to show a differential response to LABA step-up therapy. Black children were as likely to have their best response to ICS as to LABA, although white (non-Hispanic) and Hispanic children were more likely to have best response to LABA. Children without eczema were also more likely to have their best response to LABA.
During the trial, children received a total of 120 prednisone bursts (30 while on LABA, 47 on ICS, and 43 on LTRA). Three hospitalizations, 1 with each of the step-up regimens, occurred during the study. The investigators concluded that nearly all children had a differential response, and LABA step-up therapy was significantly more likely to provide a better response for an individual child than either ICS or LTRA.
This complex study provides some real practical guidance for clinicians, even more so given that few data compare asthma step-up options in children. The investigators point out that one of the main take-home points is that even though LABA appeared to offer the best chance of best response, more than 30% of children had their best response to each of the other 2 agents. Therefore, monitoring for response is important and trials of other step-up regimens are appropriate if a child does not respond to the first regimen. The study authors also point out that little intrinsic information about the patient, except perhaps race/ethnicity, can predict which regimen offers the best chance, up front, for asthma control. Both the investigators and authors of an accompanying editorial point out the concerns of sudden asthma-related death with LABAs and the resulting FDA warnings about those drugs. Because of these safety concerns and because there is a reasonable chance (at least 30%) that any child will respond better to either LTRA or ICS, the authors of the editorial recommend prescribing ICS as the first step-up regimen. In any case, clinicians now have the data necessary to make an informed discussion with parents on which step-up regimen to prescribe for the child.
Abstract
Step-up Therapy for Children With Uncontrolled Asthma Receiving Inhaled Corticosteroids
Lemanske RF, Mauger DT, Sorkness CA, et al, for the Childhood Asthma Research and Education (CARE) Network of the National, Heart, Lung, and Blood Institute.
N Engl J Med. 2010;362:975-985.
Background
Lemanske and colleagues reviewed data demonstrating that children in a clinical trial of inhaled corticosteroid (ICS) for asthma may still have periods of poor control, so some type of step-up controller therapy is often needed. Few studies have been conducted in children to guide clinicians in the selection of the step-up therapy that best controls asthma after first-line ICS.
Study Summary
This study evaluated whether any of 3 regimens for step-up controller therapy were better in children with inadequately controlled asthma. The 3 regimens were increased ICS dose, adding a long-acting beta-agonist (LABA), or adding a leukotriene-receptor antagonist (LTRA). Participants were children 6-17 years of age with mild-to-moderate asthma, all of whom met the prespecified criteria for this classification based on National Heart, Lung, and Blood Institute guidelines.
All children participated in an 8-week run-in trial, during which they took 100 µg of inhaled fluticasone per day. If that regimen did not control the asthma, the child began the 48-week comparative trial. During the 48 weeks, each child spent 16 weeks on each of the 3 regimens. During ICS step-up periods, they received 250 µg of inhaled fluticasone per day; during the LABA step-up periods, they received 100 µg of inhaled fluticasone plus 50 µg of salmeterol per day; finally, during the LTRA step-up periods, the children received 100 µg of inhaled fluticasone plus 5-10 mg of montelukast per day. The children took dummy/placebo preparations of inactive drug, plus the active drug, during each 16-week period for purposes of masking. To allow for washout when switching regimens, the investigators analyzed the last 12 weeks of each cycle to determine the degree of asthma control attributable to each regimen.
Children were allowed oral prednisone treatment for exacerbations of asthma, and they were seen routinely every 4 weeks for symptom monitoring. The investigators also measured quality of life. The goal of the study was to determine which regimen performed better as evidenced by use of oral or systemic corticosteroids; number of "asthma control days" (eg., no use of rescue medication or symptoms and peak flow variation < 20%); and higher forced expiratory volume in 1 second (FEV1). A regimen was considered better than another if, while on that regimen, the child took at least 180 mg less systemic corticosteroids, experienced an increase in asthma control of at least 31 days in the 12 weeks, or if FEV1 was at least 5% higher than on another regimen, in that order of importance. For example, if someone met the definition of "improved" by receiving less steroids, then asthma control days and FEV1 measurements were ignored. In that manner, each child’s degree of asthma control was compared with that during the other cycles.
Four hundred eighty patients were enrolled in the study. Of those, asthma was uncontrolled in 182 during the run-in period, and therefore they were eligible for the full trial. Of these 182 children, 157 (86%) completed the full trial and 165 completed at least 2 treatment cycles. Ninety-eight percent of the patients did better on at least 1 of the step-up regimens than on the other regimens. Overall, LABA was best for more patients. When comparing LABA with LTRA, 52% of children responded better to LABA and 34% responded better to LTRA. In a similar fashion, when LABA was compared with ICS, 54% of children experienced a better response on LABA compared with 32% who did better on LTRA. Performance of ICS and LTRA was almost equal.
Many factors were not predictive of a child experiencing a differential response, including degree of response to methacholine challenge, fraction of exhaled nitric oxide, or genetic markers. Children with better baseline control of asthma at study entry were more likely to show a differential response to LABA step-up therapy. Black children were as likely to have their best response to ICS as to LABA, although white (non-Hispanic) and Hispanic children were more likely to have best response to LABA. Children without eczema were also more likely to have their best response to LABA.
During the trial, children received a total of 120 prednisone bursts (30 while on LABA, 47 on ICS, and 43 on LTRA). Three hospitalizations, 1 with each of the step-up regimens, occurred during the study. The investigators concluded that nearly all children had a differential response, and LABA step-up therapy was significantly more likely to provide a better response for an individual child than either ICS or LTRA.
Viewpoint
This complex study provides some real practical guidance for clinicians, even more so given that few data compare asthma step-up options in children. The investigators point out that one of the main take-home points is that even though LABA appeared to offer the best chance of best response, more than 30% of children had their best response to each of the other 2 agents. Therefore, monitoring for response is important and trials of other step-up regimens are appropriate if a child does not respond to the first regimen. The study authors also point out that little intrinsic information about the patient, except perhaps race/ethnicity, can predict which regimen offers the best chance, up front, for asthma control. Both the investigators and authors of an accompanying editorial point out the concerns of sudden asthma-related death with LABAs and the resulting FDA warnings about those drugs. Because of these safety concerns and because there is a reasonable chance (at least 30%) that any child will respond better to either LTRA or ICS, the authors of the editorial recommend prescribing ICS as the first step-up regimen. In any case, clinicians now have the data necessary to make an informed discussion with parents on which step-up regimen to prescribe for the child.
Abstract