Balanced perspective essential in erosive oesophagitis treatment: Author's reply

Field: Medicine (Health Sciences)

Sirs, I thank Dr Gillessen for his interest in our paper detailing the results of the EXPO study. I agree, it is of interest that the previous small study claims non-inferiority for pantoprazole 40 mg relative to esomeprazole 40 mg.1 However, our much larger study has now shown that esomeprazole 40 mg is indeed superior to pantoprazole 40 mg for healing oesophagitis.2 I note that the study by Dr Gillessen was limited to patients with Los Angeles (LA) grade B and C oesophagitis and with treatment groups split into three strata, resulting in fewer than 40 patients per stratum. In addition, Dr Gillessen's claim of non-inferiority appears to ignore the guidelines of the European Medicines Evaluation Agency by using a shifting non-inferiority margin and not a prespecified margin as recommended. Dr Gillessen claims that the significant difference in healing rates for esomeprazole over pantoprazole is not clinically relevant because the difference was <5%. However, in the EXPO study, the assumption of a 5% difference in healing rates was only used to calculate the sample size for a study establishing superiority and was based on previously published healing rates from comparative trials with proton-pump inhibitors (PPIs). It was not a cut-off for the level of clinical relevance. Given the number of patients who are treated with PPIs for erosive oesophagitis, we believe the statistically significant 3.5% improvement in healing rates with esomeprazole relative to pantoprazole is clinically important and represents a clear improvement over pantoprazole for patients with erosive oesophagitis. Moreover, the difference between both PPIs was substantially greater after 4 weeks of treatment and with increasing severity of oesophagitis respectively. I am very sceptical of Dr Gillessen's conclusions based on his selective post hoc analysis of the EXPO study data; most notably, his assertion that the greater proportion of patients with LA grade A oesophagitis in the esomeprazole treatment group could have led to the difference in healing rate between esomeprazole and pantoprazole. In the EXPO study, we performed analyses ‘stratified by baseline oesophagitis severity’ (the standard statistical method to adjust for imbalances in baseline factors that may influence a comparison) and found significant differences in healing rates. Therefore, any imbalance in the distribution of severity in the study groups ‘cannot’ be an explanation for the treatment differences observed in the study. In addition, we have performed logistic regression analyses, which clearly identified choice of PPI as an independent predictor of success.3 I agree with Dr Gillessen that an integrated therapeutic perspective is required in the treatment of oesophagitis, but it is also important that clearly defined symptoms are assessed at baseline and following treatment. The assessment scale favoured in many Atlanta-funded pantoprazole studies (including the study in question by Dr Gillessen) takes no account of the severity of individual symptoms. Indeed an improvement in a patient's overall symptom score (driven by improvements in symptoms such as flatulence) could mask deterioration in a more troublesome symptom such as heartburn. Furthermore, I believe, the EXPO study also provides greater therapeutic relevance because it assessed not only the acute treatment of oesophagitis, but also, in the same patient population, the maintenance therapy with esomeprazole 20 mg or pantoprazole 20 mg. These results are detailed in a manuscript published in Alimentary Pharmacology and Therapeutics and further differentiate esomeprazole from pantoprazole for patients with erosive oesophagitis.4 Finally, there is a wealth of published data on the antisecretory potency of these two drugs derived from cross-over studies showing the superiority of esomeprazole over pantoprazole. Therefore, the EXPO study results showing esomeprazole is more effective than pantoprazole for healing erosive oesophagitis would have been expected.