Why didn’t patient with documented reflux get better with PPI?

There are numerous problems with pH studies; many of these problems have been alluded to in previous blog entries (see below).  Another problem is that these studies are not highly predictive of response to therapy (Gut 2012; 61: 501-506).

This French study from three centers examined 100 consecutive patients (58 females) with an average age of 50 years.  All patients had reflux symptoms, namely regurgitation and/or heartburn.  PPI dosage was not standardized and reflux symptoms were quantified with recall questionnaires.

The authors note that up to 40% of patients with reflux symptoms have inadequate symptom relief with a 4-week course of single dose proton pump inhibitor (PPI) therapy; the aim of their study was to investigate which factors on pH probe-impedance (pH-MII) would predict a response to therapy.

Definition: Nonresponders were patients who had more than 2 days of mild symptoms per week while receiving a standard or double dose of PPI treatment for 4 weeks


  • No reflux pattern on pH-MII was associated with a response to PPIs. Table 2 in the study looked at multiple factors including SI, SAP, time for acid exposure, and number of reflux events.
  • Lower BMI (≤ 25 kg/m-squared), non-erosive reflux, and normal pH study were associated with poor PPI response
  • Other factors associated with poor PPI response: female gender, irritable bowel syndrome (IBS), and functional dyspepsia.
  • Response rates: 58% of individuals with BMI >25, 71% with esophagitis, 23% with functional dyspepsia, 30% with IBS
  • Among responders, 77% were receiving a single dose PPI

Some of the poor response may be related to the study population.  Only 35% had abnormal acid exposure.  In total, 67% were determined to have abnormal pH studies, though this was due to a large fraction having a positive symptom-reflux association analysis.

However, this study population likely reflects a typical clinical group of patients diagnosed with GERD and demonstrates some of the shortcomings of pH-MII in clinical practice.  Even patients with abnormal pH-MII studies, the presence of functional dyspepsia and IBS were strongly associated with PPI failure.

Previous related blog entries:

HEROES trial

Impedance recommendations from PIG

Gastroesophageal Reflux: I know it when I see it

Treating reflux does not help asthma

Unexplained chest pain

10 thoughts on “Why didn’t patient with documented reflux get better with PPI?

  1. Excellent example of how convoluted the field of gastroesophageal reflux disease has become.

    Important points, or rather musings to consider;
    1) the paradigm that is being tested here is acid exposure equals disease which equals GERD; yet there is an immediate selection bias with these patients which are predominantly what are called “NERD” (non-erosive reflux disease).
    2) NERD patients are a relatively “mixed-bag” of patients many of which have a functional (i.e. Rome III criteria) component to their disease and/or symptoms, and often are not the ones that are PPI responsive irrespective of the dose, and, by definition, NERD patients have no evidence of esophageal disease which often is a pretty good indicator of the acid-disease model of GERD.
    3) the patients in the study are not “true” NERD patients in that endoscopy was not done prior to study enrollment, and the robustness and validity of the GERD recall questionnaire used in this study could be brought into question as its validity as a tool to predict treatment response;
    4) the use of impedance-pH monitoring as an outcome tool in this study could also be questioned in it’s validity to assess whether the PPI dose was adequate, when as mentioned, there was no real standardization of PPI dose, nor use of impedance to quantitatively assess adequacy or lack of intra-gastric acid suppression at the beginning of the study – in the end – did these patients really have ‘documented’ reflux at the beginning of the study.

    Thus, I am not sure if this study really answers the very good question which is: what to do when the PPI fails?

    • Thanks as usual for your thoughtful comments. Perhaps the answer to ‘what to do when PPI fails?’–stop the PPI and reassess.

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