Proton Pump Inhibitors

Proton pump inhibitors are currently the most effective medical treatment for GERD. These compounds profoundly suppress acid secretion through the inhibition of H+, K+ adenosine triphosphatase, the proton pump of the parietal cell, and the site responsible for acid production. All PPIs are substituted benzimidazoles and are prodrugs, which must be activated in the presence of acid in order to inhibit the proton pump. Unlike the H2RAs, PPIs block acid production regardless of the method of cell stimulation, thus providing a greater degree of acid suppression for a longer duration of time. This superior pharmacological effect translates into a higher efficacy rate in GERD symptom relief and healing of esophagitis. Conventional healing rates with the first four PPIs—omepra-zole, lansoprazole, rabeprazole, and pantopra-zole—have demonstrated that a once-daily morning dose of a PPI will provide relief of symptoms and healing of erosive esophagitis in approximately 80% of patients.8 Healing rates increase further when therapy is extended another 4-8 weeks. Supporting this estimate of treatment effect with PPIs is a quantitative systematic review of the comparative efficacy of PPIs and H2RAs that analyzed 23 reports comprising 5118 patients.15 The overall healing was 78% for the PPIs and 44% with H2RAs at week 8. This translated to a relative risk of 1.7 [confidence interval (CI) 1.6-1.8], and number needed to treat (NNT) was 3 (CI 2.8-3.6) for PPIs compared with the H2RAs. As with H2RAs, however, the healing rates with PPI therapy correlate inversely with the severity of esophagitis. Incremental dosing of the PPI has not been shown to increase healing or symptom response—at least when the dose is doubled but still given once a day. There are no studies of esophageal healing that have evaluated the effects of a twice-daily (BID) PPI dosing regimen. Conceptually this clinical approach should improve outcomes given the augmentation of gastric pH effect seen with BID dosing.16 Esomeprazole, the S isomer of omeprazole, has demonstrated superior pH effect versus the other PPIs and this has correlated with clinical data indicating improved clinical outcomes when this PPI is used versus lansoprazole, pan-toprazole, and omeprazole, notably healing of erosive esophagitis and symptom resolution.17 Previously, there had been few comparisons between individual PPIs that used acceptable evidence-based approaches for analysis. What data that were available showed few differences between the original four PPIs. For instance, a meta-analysis that compared omeprazole with lansoprazole found no significant difference in the healing rates between these PPIs and reported a NNT of 67.18 More recent studies involving comparison of esomeprazole to the

MEDICAL MANAGEMENT OF GERD: ALGORITHMS AND OUTCOMES

first-generation PPIs have shown clear superiority for healing—in particular for the more severe grades of esophagitis (Los Angeles grades C and D). The NNT for the more severe grades of esophagitis has ranged from 5 to 10 in the trials comparing esomeprazole to omeprazole, lansoprazole, and pantoprazole.17 Superior symptom resolution was also evident in these same trials.

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