A Prospective, Observational Study of the PPI Non-responder

Gastroesophageal reflux disease (GERD) is a common chronic condition, affecting approximately
20% of the American adult population. Gastroesophageal reflux disease is characterized by a
number of symptoms, the 2 most common being frequent heartburn and acid regurgitation.
Untreated or undertreated gastroesophageal reflux (GER) can lead to complications including
esophageal erosions, strictures, esophageal adenocarcinoma, and impaired quality of life.

Proton pump inhibitors (PPIs) are now the mainstay of medical therapy for symptoms of GERD.
Despite their efficacy, several studies have shown that a significant proportion of GERD
patients are either partial or non-responders to PPI therapy, defined as symptoms of
heartburn and/or regurgitation not relieved by either a standard or double dose of a PPI
during a minimum trial of 8 weeks. A review of 19 studies looking at GERD patients treated
with PPIs found an overall prevalence of partial and non-responders of up to 45% in
observational studies. Non-randomized studies revealed a prevalence of 17% when defined as
"persisting troublesome heartburn" and 28% when defined as troublesome regurgitation, while
randomized studies revealed prevalence rates of 32% and 28%, respectively.

Current guidelines recommend an 8-week trial of a daily PPI for the treatment of symptoms
thought secondary to GERD. However, if GERD symptoms persist despite taking the PPI
correctly, then testing is required. National guidelines recommend that patients with GERD
symptoms who have failed empiric therapy with a PPI undergo upper endoscopy (EGD). This
recommendation is based on data showing that the PPI non-responsive patient may have a
disorder (e.g., peptic ulcer disease, dyspepsia, eosinophilic esophagitis, cancer) that can
only be identified by EGD. During upper endoscopy a 48-hour wireless pH capsule can be placed
to measure acid reflux into the distal esophagus. This recommended practice has been shown to
be cost effective. If the 48 hour wireless pH capsule study documents pathologic acid reflux,
then the diagnosis of acid reflux is confirmed and the patient should be restarted on a PPI
with appropriate counseling regarding how to take a PPI properly. Switching the patient to an
alternative PPI is a reasonable strategy, as some patients respond better to one PPI than
another . In addition, during this index endoscopy, biopsies of the esophagus should be taken
to rule out eosinophilic esophagitis.

Some patients in clinical practice have previously undergone testing due to their GERD
symptoms. In patients with proven GERD (e.g., prior EGD with LA Grade B-D esophagitis, known
Barrett's esophagus, prior positive pH tests either on or off PPI therapy) who continue to
have GERD symptoms on a daily PPI, guidelines recommend that impedance pH-testing be
performed on daily PPI therapy. Guidelines do not recommend testing on b.i.d. PPI therapy,
since most patients with GERD do not require twice-daily PPI therapy. In this patient
population (the PPI non-responder with proven GERD), impedance-pH testing is preferable to
48-hour wireless pH capsule testing as non-acid reflux can be detected as well. To be cost
effective, and to reduce the number of unnecessary EGDs, if upper endoscopy was recently
performed, then impedance-pH testing can be performed after accurate localization of the
lower esophageal sphincter using high resolution esophageal manometry (HREM). If the
impedance-pH test is negative (normal) on daily PPI therapy, demonstrating that acid reflux
is controlled, then a second diagnosis should to be considered (e.g., functional dyspepsia,
gastroparesis, an esophageal motility disorder). If impedance-pH monitoring demonstrates
abnormal acid reflux on daily PPI therapy, then guidelines recommend that the PPI dose should
be increased to twice daily and symptoms reassessed at 8 weeks.

The clinical treatment pathways outlined above are based on national guidelines and are
promoted as standards of care. However, despite the fact that these guidelines recommend
distinct diagnostic pathways for patients who are non-responsive to PPIs, there is little
"real-world" data to support these guidelines and no information about the outcomes of these
patients who are treated using these diagnostic pathways. The simple goal of this study is to
identify the PPI non-responder patient with GERD symptoms and identify and quantify the type,
number and outcomes of diagnostic tests recommended by national guidelines.

Inclusion Criteria:

- Willing and able to sign informed consent

- Persistent GERD symptoms after minimum 8 week trial on daily PPI

Exclusion Criteria:

- Unwilling to sign informed consent

- Prior anti-reflux surgery