Management of the patient with incomplete response to PPI therapy

Abstract

Proton pump inhibitors (PPIs) remove most of the acid from the gastroesophageal refluxate. However, PPIs do not eliminate reflux and the response of specific GERD symptoms to PPI therapy depends on the degree to which acid drives those symptoms. PPIs are progressively less effective for heartburn, regurgitation, chest pain and extra-oesophageal symptoms. Hence, with an incomplete PPI response, obtaining an accurate history, detailing which symptoms are 'refractory' and exactly what evidence exists linking these symptoms to GERD is paramount. Reflux can continue to cause symptoms despite PPI therapy because of persistent acid reflux or weakly acidic reflux. Given these possibilities, diagnostic testing (pH or pH-impedance monitoring) becomes essential. Antireflux surgery is an alternative in patients if a clear relationship is established between persistent symptoms, particularly regurgitation, and reflux. Treating visceral hypersensitivity may also benefit the subset of GERD patients whose symptoms are driven by this mechanism.

Keywords: Ambulatory oesophageal pH monitoring; Ambulatory oesophageal pH-impedance monitoring; Gastroesophageal reflux disease; Oesophagus; Proton pump inhibitors; Visceral hypersensitivity.

Figure 1

Conceptual model of the pathophysiological triggers of GERD symptoms. The fundamental abnormalities are of symptomatic reflux events and prolonged clearance. However, the effect of reflux in eliciting symptoms is linked to the toxicity of gastric juice even though this factor is usually normal in GERD patients. Acid clearance and mucosal sensitivity modulate the effect of reflux by prolonging the exposure of the esophageal mucosa to refluxate and diminishing the sensory threshold of what is perceived as painful. Modified from [8].

Figure 2

Summary of PPI efficacy for various GERD syndromes as assessed in randomized controlled trials. In each case, data among trials are averaged to derive estimates of placebo effect and therapeutic gain, defined as the degree to which PPI therapy improved upon the benefit seen with placebo. The blue segments represent the placebo effect and the green arrows the therapeutic gain beyond the placebo effect seen with PPIs. PPI data are grouped in terms of brand and dose, taking some liberties for simplification. However, it is imperative to recognize that the only disease manifestation in which a dose-response curve has been convincingly demonstrated by randomized controlled trial is in healing esophagitis. At the other extreme, in the case of hoarseness, controlled trial data are sparse and the only large trial (which was done in patients without esophagitis or frequent heartburn) failed to show benefit of PPI vs placebo [17]. Modified from [8].

Figure 3

Algorithm for management of the patient with incomplete response to PPI therapy. Since the pivotal question in ‘therapy-refractory GERD’ is whether or not the symptoms are attributable to reflux, pH/impedance monitoring plays a central role in the evaluation. The chance of finding a positive correlation between symptoms and reflux events is greatest when the reflux monitoring is carried out ‘off’ acid inhibition therapy. Antireflux surgery is best restricted to patients with pathological reflux and a positive symptom correlation.