Randomized Controlled Trial of Esomeprazole in Functional Dyspepsia Patients with Epigastric Pain and Burning

Abstract & Commentary

By Malcolm Robinson MD, FACP, FACG, Emeritus Clinical Professor of Medicine, University of Oklahoma College of Medicine, Oklahoma City. Dr. Robinson reports no financial relationship to this field of study.

Synopsis: One week of acid suppression, even with esomeprazole 40 mg bid, fails to predict longer term symptom response in functional dyspepsia.

Source: Talley NJ, et al, on behalf of the STARS I Study Group. Alimentary Pharm Ther. 2007;26:673-682.

Patients with upper abdominal burning pain, nil or minimal GERD symptoms, and normal endoscopy were entered in this study. After exclusions including abnormal endoscopy (n = 635 with 407 cases of esophagitis), insufficient symptoms during run-in (n = 343), or unacceptably prominent GERD symptoms during run-in (n = 50), 1589 patients were randomized to three treatment arms. Initial study groups were esomeprazole 40 mg each morning (n = 617), 40 mg morning and evening (n = 649), and placebo (n = 623). Week 1 response was assessed as either no symptoms or mild symptoms during the last 3 days of the first week of therapy. Responses for the 3 study groups at Week 1 were 33%, 29%, and 23% respectively (NS). For the next 7 weeks of the study, all patients were re-randomized to 40 mg ESO daily or placebo. Responses at Week 4 or Week 8 required a rigorous 0 or 1 for the sum of the symptoms recorded during the 7 days prior to evaluation. At Week 4, rates of successful response were 26% for ESO recipients vs 25% for those on placebo (NS). At 8 weeks, the patients on ESO had significantly better symptom resolution than those on placebo (39% vs 29%, p = 0.015). In sub-analyses of the data, it was clear that presence of any heartburn and/or regurgitation at baseline led to much of the efficacy seen in the group as a whole. Safety was not an issue although one patient on placebo died of metastatic cancer during the 7-week treatment period.

Commentary

Although academic gastroenterologists describe "dyspepsia" as very common in the community, most clinicians don't actually diagnose this entity (nor would most patients have the slightest idea of what "dyspepsia" would imply). A number of the authors of this study have taught us that there is a tremendous real life overlap between "ulcer" symptoms, GERD, and IBS. Patients seldom have (and even more seldom can describe) absolutely pure symptoms of these entities. When endoscopy is normal, the situation is even more muddled with many GERD symptoms in ulcer-like dyspepsia patients and vice versa. This phenomenon undoubtedly explains the frequency of exclusions from the study (both on the basis of "incorrect" symptoms or unexpected endoscopy findings). If these same authors had been studying functional heartburn, I suspect that many of the same patients that were entered into this "dyspepsia" study would have qualified and entered (although possibly in other months or years of their chronic GI complaints). In their Discussion, the authors essentially admit this. It is important to recognize that there was a companion study to STARS I known as STARS II.1 STARS II was similar to STARS I except for the absence of endoscopy pre-entry: ie, uninvestigated symptomatic H. pylori negative patients. Results of this trial also appeared in the same journal issue and demonstrated similarly poor predictive value of the 1-week response to esomeprazole (ESO) 40 mg or 80 mg daily for longer term success or failure (at 4 or 8 weeks). The 1-week results for symptomatic response to 40 mg of ESO indicated 39% response, and 1-week response to 80 mg daily was 43%. Most of the patients actually failed to respond to either dose of ESO at 4 or 8 weeks although those with any heartburn or defined "burning" epigastric pain seemed to do better than those with other symptom patterns. Positive and negative predictive values were unacceptably low in both STARS 1 and STARS II studies. Although the authors of these studies stressed the fact that ESO did have some benefits vs placebo in these endoscopy-negative dyspeptic patients, a totally different conclusion seems obvious to me. Most patients with non-ulcer dyspepsia respond modestly or not at all to acid suppression, including quite aggressive acid suppression. GERD and its symptoms are the most dependable markers for success with ESO (or other PPIs). Indeed, the authors of these studies declared that their unimpressive response rates to ESO were probably due to their success in excluding most GERD from their studies. In any case, the response to single or double dose ESO during the first week of therapy is not a valid determinant for long term efficacy of continued ESO treatment (or other PPI treatment). We need better markers for the various subtypes that comprise the multiple disease entities that all fall under the heading of dyspepsia.

Reference

1. van Zanten SV, et al, on behalf of the STARS II Study Group. Aliment Pharmacol Ther. 2007;26:665-672.