Safety and Efficacy of PPIs in Severe Acid-peptic Disease
Background To date, the safety and tolerability of proton pump inhibitors (PPIs) have been demonstrated in studies of up to 10 years.
Aim To report on the tolerability, safety and efficacy of up to 15 years' continuous treatment with pantoprazole in patients with severe acid-peptic disease.
Methods Following healing of endoscopically confirmed peptic ulcer or reflux oesophagitis during 4–12 weeks' treatment with pantoprazole (40–80 mg/day), adult patients received open-label maintenance treatment with pantoprazole (40–160 mg/day) for up to 15 years in a single centre combined study (10-year initial study; 5-year extension study). Safety assessments were carried out using endoscopy, clinical examination, clinical laboratory investigations, serum gastrin determination, gastric mucosal histology and mucosal endocrine cell quantification.
Results The safety set comprised 142 patients. At 12 weeks, healing rates were 95.8%. During long-term treatment, mean fasting gastrin levels rose from baseline to moderate levels throughout the study. Mean enterochromaffin-like cell density showed a moderate initial increase during the first 3 years, remaining stable thereafter. These changes were not associated with any clinically relevant changes of the gastric mucosa. Patients with successful Helicobacter pylori eradication showed long-term regression of antral and corpus gastritis during continued pantoprazole treatment.
Conclusions Daily pantoprazole maintenance therapy for up to 15 years for severe acid-peptic disease is effective and well tolerated, with no identified safety concerns. The longest study to date, these data provide reassuring evidence for the long-term safety of pantoprazole.
The proton pump inhibitor (PPI) pantoprazole was first approved for the treatment of gastric and duodenal ulcer in Germany in 1994. Thus, when this study commenced in 1990, little was known of its efficacy and safety in the management of acid-related peptic disorders. Subsequently, the short-term efficacy and safety of pantoprazole has been well established in pivotal clinical trials, and up to 5 years' treatment with pantoprazole has been investigated. Furthermore, PPIs have become the treatment of choice in acid-related peptic disorders.
Nonetheless, there has been concern that the long-term use of acid suppression therapy may lead to progressive changes in gastric mucosal histology and subsequent development of gastric carcinoma. Initial reservations were mainly based on rat toxicity studies conducted during the development of PPIs, which showed that animals receiving continuous long-term administration of high doses of omeprazole frequently developed enterochromaffin-like (ECL) cell carcinoid tumours. Furthermore, in 1996, Kuipers et al. reported that long-term treatment with omeprazole increased the risk of developing atrophic gastritis in patients with Helicobacter pylori infection, thus potentially leading to the later development of gastric adenocarcinoma. However, the results of Kuipers et al. were not confirmed in subsequent studies and an advisory panel to the US Food and Drug Administration came to the conclusion that no changes in the usage of PPI therapy were indicated.
More recently, clinical studies evaluating the long-term administration of various PPIs have been performed suggesting that these safety concerns may be unfounded with up to 10 years' PPI treatment. In the longest study to date, here we report on the tolerability, safety and efficacy of up to 15 years' treatment with pantoprazole in patients with severe acid-peptic disease.
Abstract and Introduction
Abstract
Background To date, the safety and tolerability of proton pump inhibitors (PPIs) have been demonstrated in studies of up to 10 years.
Aim To report on the tolerability, safety and efficacy of up to 15 years' continuous treatment with pantoprazole in patients with severe acid-peptic disease.
Methods Following healing of endoscopically confirmed peptic ulcer or reflux oesophagitis during 4–12 weeks' treatment with pantoprazole (40–80 mg/day), adult patients received open-label maintenance treatment with pantoprazole (40–160 mg/day) for up to 15 years in a single centre combined study (10-year initial study; 5-year extension study). Safety assessments were carried out using endoscopy, clinical examination, clinical laboratory investigations, serum gastrin determination, gastric mucosal histology and mucosal endocrine cell quantification.
Results The safety set comprised 142 patients. At 12 weeks, healing rates were 95.8%. During long-term treatment, mean fasting gastrin levels rose from baseline to moderate levels throughout the study. Mean enterochromaffin-like cell density showed a moderate initial increase during the first 3 years, remaining stable thereafter. These changes were not associated with any clinically relevant changes of the gastric mucosa. Patients with successful Helicobacter pylori eradication showed long-term regression of antral and corpus gastritis during continued pantoprazole treatment.
Conclusions Daily pantoprazole maintenance therapy for up to 15 years for severe acid-peptic disease is effective and well tolerated, with no identified safety concerns. The longest study to date, these data provide reassuring evidence for the long-term safety of pantoprazole.
Introduction
The proton pump inhibitor (PPI) pantoprazole was first approved for the treatment of gastric and duodenal ulcer in Germany in 1994. Thus, when this study commenced in 1990, little was known of its efficacy and safety in the management of acid-related peptic disorders. Subsequently, the short-term efficacy and safety of pantoprazole has been well established in pivotal clinical trials, and up to 5 years' treatment with pantoprazole has been investigated. Furthermore, PPIs have become the treatment of choice in acid-related peptic disorders.
Nonetheless, there has been concern that the long-term use of acid suppression therapy may lead to progressive changes in gastric mucosal histology and subsequent development of gastric carcinoma. Initial reservations were mainly based on rat toxicity studies conducted during the development of PPIs, which showed that animals receiving continuous long-term administration of high doses of omeprazole frequently developed enterochromaffin-like (ECL) cell carcinoid tumours. Furthermore, in 1996, Kuipers et al. reported that long-term treatment with omeprazole increased the risk of developing atrophic gastritis in patients with Helicobacter pylori infection, thus potentially leading to the later development of gastric adenocarcinoma. However, the results of Kuipers et al. were not confirmed in subsequent studies and an advisory panel to the US Food and Drug Administration came to the conclusion that no changes in the usage of PPI therapy were indicated.
More recently, clinical studies evaluating the long-term administration of various PPIs have been performed suggesting that these safety concerns may be unfounded with up to 10 years' PPI treatment. In the longest study to date, here we report on the tolerability, safety and efficacy of up to 15 years' treatment with pantoprazole in patients with severe acid-peptic disease.
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