To the editors:

We thank Savarino et al. for their interest in our meta-analysis. In their letter, these authors emphasize the fact that patients with reflux symptoms and negative endoscopy do not always have gastro-esophageal reflux disease (GERD), but instead often suffer from functional heartburn, a disorder in which the symptoms are not related to reflux of gastric content. It is obvious that these patients will not respond to acid suppression.1 They also describe that in part of the true non-erosive reflux disease (NERD) patients, the symptoms are induced by weakly acidic reflux and that this is the reason these patients do not respond to acid suppression.2,3 The authors call for better characterization of patients with reflux symptoms before inclusion into clinical trials, preferably by pH-impedance monitoring.

We agree that for clinical trials comparing the efficacy of therapies for GERD, both medical and surgical, it is essential to characterize the study population carefully. When it is desired to test the effect in true GERD patients, it is essential to perform reflux monitoring in the non-erosive patients. This can be done with either pH-monitoring or pH-impedance monitoring. If this is performed off proton pump inhibitor (PPI), pH monitoring alone is sufficient, given that it is very rare for patients to only have symptoms due to weakly acidic reflux while they are not using PPI during the measurement.4 The advantage of such careful patient selection is that the measured efficacy of the intervention will be higher. However, disadvantages are that patient inclusion will be more difficult and the results of such a trial are difficult to extrapolate to the general population in whom no additional testing is performed. Alternatively, one can include patients by just using the presence of typical reflux symptoms. This makes the inclusion of a large number of patients easier and the results are generalizable to the large population with these symptoms. However, the measured efficacy of the intervention will be less predictable due to the heterogeneity of the studied population. It also has the implication that for a negative trial result, it is not clear if this is because of a lack of efficacy or because the study population is polluted by patients who do not have the disease. Taking the above into account, we agree on inclusion of reflux monitoring in future GERD trials.


  1. Top of page
  2. Disclosures
  3. References

P. Weijenborg: no conflicts of interest exist; F. Cremonini: no conflicts of interest exist; A. Smout: no conflicts of interest exist; A. Bredenoord: research funding of Astra Zeneca and Movetis-Shire; lecture fees of AstraZeneca and MMS.


  1. Top of page
  2. Disclosures
  3. References
  • 1
    Weijenborg PW, Cremonini F, Smout AJPM, Bredenoord AJ. PPI therapy is equally effective in well-defined non-erosive reflux disease and in reflux esophagitis: a meta-analysis. Neurogastroenterol Motil 2012; 24: 747e350.
  • 2
    Savarino E, Tutuian R, Zentilin P et al. Characteristics of reflux episodes and symptom association in patients with erosive esophagitis and nonerosive reflux disease: study using combined impedance–pH off therapy. Am J Gastroenterol 2009; 105: 105361.
  • 3
    Woodland P, Sifrim D. The refluxate: the impact of its magnitude, composition and distribution. Best Pract Res Clin Gastroenterol 2010; 24: 86171.
  • 4
    Hemmink GJM, Bredenoord AJ, Weusten BLAM, Monkelbaan JF, Timmer R, Smout AJPM. Esophageal pH-impedance monitoring in patients with therapy-resistant reflux symptoms: “on” or “off” proton pump inhibitor? Am J Gastroenterol 2008; 103: 244653.
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