Safety and tolerability of high-dose intravenous esomeprazole for prevention of peptic ulcer rebleeding

Introduction: Efficacy of a continuous high-dose intravenous infusion of esomeprazole, followed by an oral regimen after successful endoscopic therapy for peptic ulcer bleeding (PUB) was established in the PUB study (ClinicalTrials. gov identifier: NCT00251979). Mortality rates and detailed safety and tolerability results from this study are reported here. Methods: This was a double-blind, randomized study in patients ≥18 years with overt signs of upper gastrointestinal bleeding, following endoscopic diagnosis of a single gastric or duodenal ulcer (≥5 mm) with stigmata indicating current/ recent bleeding (Forrest class Ia, Ib, IIa, or IIb). Postendoscopic hemostasis, patients received intravenous esomeprazole (80 mg/30 minutes, then 8 mg/hour for 71.5 hours) or placebo. Postinfusion, all patients received open-label oral esomeprazole 40 mg once daily for 27 days. Mortality rates were analyzed using Fisher's exact test; other safety variables were analyzed descriptively. Results: A total of 767 patients were randomized; 764 comprised the safety analysis set (375 patients received esomeprazole, 389 placebo). Baseline characteristics were similar across the two treatment groups. Three deaths from the esomeprazole treatment group and eight from the placebo group occurred during the trial (0.8% versus 2.1%; P=0.22). From these 11 all-cause deaths, one (esomeprazole group; rebleeding from duodenal ulcer) occurred during the 72-hour intravenous treatment phase. Adverse event (AE) frequency was similar for the two groups over the intravenous treatment phase (esomeprazole, 39.2%; placebo, 41.9%), with gastrointestinal disorders being most commonly reported (12.3% and 19.8%, respectively). Serious AEs were mostly related to bleeding events. Infusion-site reactions (mild, transient) were reported in 4.3% of esomeprazole-treated patients versus 0.5% of placebo patients. These did not lead to treatment discontinuation. Conclusion: Esomeprazole, given as a continuous high-dose intravenous infusion followed by an oral regimen after successful endoscopic therapy for PUB, was well tolerated, with no apparent safety concerns from either the high-dose intravenous treatment or oral phases.