Pantoprazole for Symptoms of Infant GERD: The Emperor Has No Clothes!

To the Editor: To date, no reliable study shows clear efficacy of proton pump inhibitor (PPI) for symptoms of gastroesophageal reflux disease (GERD) in infants. This remains the case despite the conclusions of Winter et al (1) in their study of pantoprazole, published in JPGN June 2010, which concludes that “Pantoprazole significantly improved GERD symptom scores,” and “short-term open-label treatment with pantoprazole in infants with GERD symptoms was effective in reducing these symptoms.” It is naïve (or perhaps conflicted) to conclude that the drug has efficacy based on a 4-week open-label (uncontrolled) portion of a study, particularly in light of the considerable efficacy of placebo in a similar group of infants in another study (2), and also in light of the pantoprazole study's failure to detect a clinically significant difference between pantoprazole and placebo in the subsequent 4-week withdrawal phase. Taking these issues into consideration, the success of treatment claimed by the authors for the first phase of the study looks like a simple placebo response, and/or due to the effects of maturation, a possibility they acknowledge. The mass of data and statistical analysis presented in this article (1) cannot camouflage or rectify post hoc the basic design flaw of failing to include a placebo-control group from the outset. The authors state: “No data from large randomized clinical trials of the use of PPIs in infants have been published.” This is erroneous. Remarkably, the article does not reference our large, parallel group, double-blind (nonwithdrawal) study of lansoprazole that showed no efficacy in a similar group of infants (2,3). The pantoprazole paper (1) was accepted for publication on July 25, 2009, that is, subsequent to publication of our article (2), the findings of which had also been presented at North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) in 2008 (3). This is a crucial omission, and one that should have been corrected before publication. Without such consideration, and without the highlighting of the differences in the 2 study designs, a hurried reader may conclude that pantoprazole differs from lansoprazole by actually demonstrating efficacy for symptomatic infantile GERD. There is no evidence that this is the case. The authors cite the old NASPGHAN guidelines. The current NASPGHAN-ESPGHAN guidelines (4) were published in October 2009, having been previously circulated to the membership for comment long before the authors' manuscript was accepted. The authors thus had plenty of time to update their citation and to note the comments in the more recent guidelines regarding the absence of data supporting efficacy of acid suppression in infants, and the special concerns regarding risks of acid suppression in this age group. The authors have clearly devoted a great deal of time and work to this study, and have presented the results in considerable careful detail; however, this effort is for naught without adequate critical analysis and discussion of the results. There is an epidemic of overtreatment of infants with PPIs (5). This overtreatment is not without potential adverse consequences, documented by a body of evidence available before this pantoprazole study was submitted (5). We believe it is irresponsible to perform trials of PPIs that are not placebo-controlled in this group. Furthermore, JPGN should insist on a more rigorous interpretation of data, as well as on currency of discussion and referencing. In the absence of such insistence, and of placebo-controlled data, patients will continue to be subjected to the risks of treatment based on hopeful theories rather than on proven efficacy. They deserve better.

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