The More You Know, the Less You Know

The practice of medicine is just that….I advise the recommended treatment based on the information available at the time.  If I look back to the time during my fellowship in the early 90’s, much of what we thought was true and now 20 years later, been disproven.  As an example, the following study from a respected medical journal cautions against the use of PPI medication for reflux in children.  It’s worth your attention, but first some background information.

Children have a high prevalence of asthma and gastroesophageal reflux (GER). Children with asthma often report symptoms of GER and also have a high prevalence of asymptomatic GER.  We call this “silent reflux”. 

Some experts have suggested that untreated GER may cause persistent asthma control problems in children refractory to treatment with inhaled corticosteroids. However, whether treatment with proton pump inhibitors (PPIs) improves asthma control has not previously been determined. The objective of this study by Holbrook and colleagues was to determine whether lansoprazole is effective in reducing asthma symptoms in children without overt GER.  (ie, Prevacid for “silent reflux”)

Study Synopsis and Perspective

Use of PPIs in children with poorly controlled asthma who were using inhaled corticosteroids and who had no symptoms of GER was not found to improve asthma control and was, in fact, associated with an increase in adverse effects, according to results of a study published in the January 25 issue of JAMA. (PPIs Produce Negative Outcomes in Children With Poor Asthma Control)

PPIs “are often prescribed for poorly controlled asthma regardless of reflux symptoms, and there have been large increases in the use of PPIs among children between 2000 and 2005…. Hence, it is of clinical importance to determine whether antireflux therapy, the most common of which are PPIs, improves control of asthma in children,” write Janet T. Holbrook, MPH, PhD, from the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and colleagues from the Writing Committee for the American Lung Association Asthma Clinical Research Centers.

The goal of this placebo-controlled, double-masked, randomized study was to determine whether the PPI lansoprazole was effective in controlling asthma symptoms in children with asthma, but no overt GER. The researchers also investigated whether pH testing would identify children with GER who responded to PPI therapy.

The children were randomly assigned to receive either lansoprazole (15 mg/day for those weighing <30 kg; 30 mg/day for those weighing ≥30 kg; n = 149) or a matching placebo (n = 157). The researchers found that the mean difference in the Asthma Control Questionnaire (ACQ) score between the 2 groups was 0.2 units (95% confidence interval [CI], 0.0 – 0.3 units), which was not statistically significant (P = .12).

There also was no significant difference in the forced expiratory volume in the first second (FEV1; 0.0 L; 95% CI, −0.1 to 0.1 L), and no change in the rate of episodes of poor asthma control (relative risk [RR], 1.2; 95% CI, 0.9 – 1.5) or asthma-related quality of life (−0.1; 95% CI, −0.3 to 0.1). In addition, children treated with lansoprazole developed more respiratory infections (RR, 1.3; 95% CI, 1.1 – 1.6; P = .02) than those in the placebo group.

A subgroup of children in the study (n = 115) underwent esophageal pH studies before randomization; the prevalence of GER among this group was found to be 43%. In those children with a positive pH study, there was no positive treatment effect with lansoprazole vs placebo for any asthma outcome.

The most common adverse event reported among both groups was asthma exacerbation.

  • This is the exact opposite of what I would expect!

A higher prevalence of upper respiratory tract infections, sore throats, and episodes of bronchitis was noted among patients in the lansoprazole group. The study authors speculate that this may be a result of loss of host defense against bacterial colonization as a result of higher gastric pH levels.

“The results of this clinical trial are uniformly negative regarding the benefit of acid suppression therapy on symptom relief, lung function, airway reactivity, or quality of life,” write the authors. The results also “indicate that PPI therapy for poorly controlled asthma is not warranted.”

In an accompanying editorial, Fernando Martinez, MD, from the Arizona Respiratory Center, University of Arizona, Tucson, notes that although it is not a statistically significant difference, the increase in activity-related bone fractures in the lansoprazole group also raises concerns. This potential complication has prompted an advisory from the US Food and Drug Administration about the risk for fractures in adults receiving chronic PPI therapy.

Overall, however, Dr. Martinez praises the work of Dr. Holbrook and colleagues and concludes that “[g]iven their potential adverse effects, these medications should thus be used with great restraint for treatment of GER/[gastroesophageal reflux disease] during childhood. The substantial increase in use of PPIs in children during the last decade is worrisome and unwarranted.”

Support for this study was provided by the American Lung Association Asthma Clinical Research Centers Infrastructure Award and National Institutes of Health/National Heart, Lung, and Blood Institute grants. Dr. Holbrook and colleagues have disclosed no relevant financial relationships. Dr. Martinez has served as a consultant to MedImmune and has presented at an Abbott-sponsored seminar.

JAMA. 2012;307:373-381, 406-407.

Study Highlights

  • The Study of Acid Reflux in Children With Asthma was a randomized, masked, placebo-controlled, parallel clinical trial comparing lansoprazole vs placebo in children without overt GER but with poor asthma control despite treatment with inhaled corticosteroids.
  • Lung function measures, such as FEV1, asthma-related quality of life, and episodes of poor asthma control, were secondary endpoints.
  • In the subgroup with a positive pH study result, there was no apparent treatment effect for lansoprazole vs placebo for any asthma outcome, including asthma-related quality of life or lung function.
  • Lansoprazole was also ineffective in subgroups defined by markers of asthma severity (either FEV1 at baseline or oral corticosteroid use in the past year).
  • At least 1 serious adverse event occurred in 10 participants in the lansoprazole group and 9 in the placebo group.
  • Asthma exacerbation was the most common serious adverse event in both groups (15 of 25 reports).
  • The investigators concluded that in children with poorly controlled asthma without symptoms of GER who were using inhaled corticosteroids, the addition of lansoprazole did not reduce symptoms or improve lung function but was associated with increased adverse events.
  • The findings do not support routine esophageal pH testing to identify children who respond to PPIs, nor do they support trials of PPIs for poorly controlled asthma.
  • An accompanying editorial notes that the overuse of PPIs in childhood asthma is an example of “therapeutic creep,” or extending the use of a treatment with real or suggestive therapeutic effects in selected patients to other patients in whom the efficacy of that treatment has never been demonstrated.
  • The editorial also notes that therapeutic creep increases the risk for potential adverse effects without any added advantage for patients and may have significantly added to the marked increase in asthma drug costs.

Clinical Implications

  • Findings of a randomized, placebo-controlled trial suggest that PPI treatment of children with poorly controlled asthma but without symptomatic GER is not effective in reducing asthma symptoms or improving lung function.
  • In this randomized, placebo-controlled trial, the addition of lansoprazole was associated with increased adverse events, particularly respiratory tract infections. There may be significant safety concerns for long-term PPI use in children, meriting further research
  • I personally wonder if more aggressive use of Vitamin D replacement would be helpful for the increase in risk of fractures for the patients taking PPI medication.  Yes indeed, further research is warranted. 

Full reference on the dangers of PPI medications

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