The proton pump inhibitor lansoprazole was no better than placebo for improving symptoms and lung function in a randomized, placebo-controlled trial involving more than 300 children with poorly controlled asthma without overt gastroesophageal reflux.
Those treated with lansoprazole did, however, experience significantly more respiratory infections (relative risk, 1.3), sore throats (RR, 1.3), and episodes of bronchitis (RR, 2.2) than did those receiving placebo during the course of the 24-week study. The treatment group also experienced more activity-related bone fractures (6 vs. 1 in treatment vs. placebo groups, respectively), although this difference did not reach significance, Dr. Nicola Hanania and her colleagues from the Writing Committee for the American Lung Association Asthma Clinical Research Centers reported in the Jan. 25 issue of JAMA.
The mean difference in change in Asthma Control Questionnaire scores between the 149 children treated with 15-30 mg/day of lansoprazole depending on weight and the 157 who received placebo in the Study of Acid Reflux in Children With Asthma was 0.2 units, which was less than the meaningful clinically important difference in both groups (–0.1 for lansoprazole, and –0.2 for placebo), and was not statistically significant. Mean differences in change for secondary outcomes, including forced expiratory volume in the first second, asthma-related quality of life, and rate of episodes of poor asthma control, also did not differ significantly between the groups, Dr. Hanania of Baylor College of Medicine, Houston, and her colleagues reported (JAMA 2012;307:373-81).
Additionally, lansoprazole had no treatment effect, compared with placebo, in a subanalysis of 49 study participants (20 in the placebo group and 29 in the lansoprazole group) who were found on esophageal pH studies to have gastroesophageal reflux (GER), they noted.
Untreated GER has been considered a possible cause of inadequate asthma control in children treated with inhaled corticosteroids, but proton pump inhibitors (PPIs) have not been well studied with respect to their use for asymptomatic GER in children with refractory asthma.
For the current double-masked study, children were enrolled between April 2007 and September 2010 at 19 academic clinical centers throughout the United States. They had a mean age of 11 years (range 6-17 years), 50% were black, 65% were boys, and all were using inhaled corticosteroids. Most had required an intervention for asthma symptoms in the year prior to enrollment, and the mean Asthma Control Questionnaire score was high, at 1.6 for both groups, which is consistent with poor asthma control.
The lansoprazole dose used for the study was based on weight, with patients weighing less than 30 kg receiving 15 mg/day, and those weighing 30 kg or more receiving 30 mg/day.
The findings indicate that the drug has no effect on asthma control measures, the investigators wrote. “This was the case even though GER was prevalent in the study sample,” they noted. It was also the case in subgroups defined by markers of asthma severity.
“The results of this clinical trial are uniformly negative regarding the benefit of acid suppression therapy on symptom relief, lung function, airways reactivity, or quality of life,” they said, concluding that in light of previous negative findings from a study of omeprazole, the use of PPI therapy in children with poorly controlled asthma is unwarranted.
The findings also raise important questions about the adverse effects of lansoprazole in children, and along with other concerning data that have led to two U.S. Food and Drug Administration Advisory Board Reviews in the past 2 years, they underscore the need for continued study of PPI safety in children, they said.
Although the activity-related fractures in the lansoprazole group were not significantly more common than in the placebo group (6 of 149 [4%] vs. 1 of 157 [less than 1%]; P = .06), they are a cause for concern. Of the seven fractures, one occurred on the day of randomization; the others occurred after 2 months (n = 1), 5 months (n = 3), and 6 months (n = 2) of follow-up. The affected children were 7-14 years old, and all had been taking inhaled corticosteroids during the trial; two had taken oral prednisone as well (one in each group).
Findings Highlight Problem of “Therapeutic Creep.” In an accompanying editorial, Dr. Fernando D. Martinez wrote that despite “unimpressive evidence” derived largely from anecdotal experience in regard to a consistent role of gastroesophageal reflux in asthma morbidity, children with asthma often are treated with antireflux medications (JAMA 2012;307:406-7). One study demonstrated that 13- to 14-year-old children with asthma were more than eight times more likely to be treated with antireflux therapy than those without asthma, said Dr. Martinez, who is at the Arizona Respiratory Center, BIO5 Institute and Clinical and Translational Science Institute at the University of Arizona, Tucson.
The practice represents “therapeutic creep” – or the extension of the use of a treatment with real or suggestive therapeutic effects observed in a certain age group or certain disease phenotype to other patients in whom the efficacy has never been demonstrated – and its perils and costs are highlighted in this study by Dr. Hanania and her colleagues, Dr. Martinez said.
Children in the study who were treated with lansoprazole were more likely than those treated with placebo to experience a number of adverse effects, including respiratory infections – without any improvement in asthma symptoms. Of even greater concern was a finding of increased activity-related bone fractures in the lansoprazole group, Dr. Martinez said, noting that this is the first large randomized controlled trial to look at this potential complication of PPIs in children.
Although the finding didn’t reach statistical significance, it should be considered “in the framework of a substantial body of evidence that has prompted the U.S. Food and Drug Administration to issue an advisory about the risk of fractures in adults taking PPIs chronically,” he said.
The findings of this study should strongly discourage the generalized use of PPIs for treating asthma, and a tentative recommendation by the current U.S. National Heart, Lung, and Blood Institute guidelines for an empirical trial of antireflux therapy in patients with poorly controlled asthma – based on the few data available at the time the guidelines were written – should be promptly revised, Dr. Martinez concluded. (The discussion continues in an exclusive video interview with Dr. Janet T. Holbrook, of The Johns Hopkins University.)
This study was supported by the American Lung Association Asthma Clinical Research Centers, as well as by grants from the U.S. National Institutes of Health/National Heart, Lung, and Blood Institute. Lansoprazole and placebo were provided by Takeda Pharmaceuticals; albuterol was provided by GlaxoSmithKline. Dr. Hanania and her coauthors had no disclosures to report.
Dr. Martinez has served as a consultant to MedImmune and has presented at an Abbott-sponsored seminar.
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