Independent Predictors for the Development of Upper Gastrointestinal Ulcers: Results from Two 24-Week Double-Blind Trials of a Single-Tablet Combination of Ibuprofen-Famotidine vs. Ibuprofen Alone

Abstract

Purpose: Although a number of observational studies provide data on risk factors for the development of upper gastrointestinal (GI) complications in NSAID users, there are scant data identifying independent risk factors for the development of ulcers at endoscopy among NSAID users. We determined predictors for the development of upper GI ulcers among NSAID users in two large 24-week double-blind prospective trials of identical design (REDUCE-1 and REDUCE-2). Methods: Patients 40-80 yrs expected to require daily NSAID therapy ≥ 6 months with no history of ulcer complications, a negative H. pylori stool antigen test and baseline EGD showing no ulcers and <5 erosions in the upper GI tract were randomly assigned in a 2:1 ratio to HZT-501 [a single tablet combination of ibuprofen (800 mg) and famotidine (26.6 mg)] or identical-appearing ibuprofen (800 mg) tablets thrice daily. Concomitant low-dose aspirin (< or = 325 mg daily) and anticoagulant therapies were permitted. Randomization was stratified based on aspirin/anticoagulant therapy and prior ulcer history. Study EGDs were done at 8, 16 and 24 weeks of therapy. The predefined population for primary analyses of ulcers was all patients with at least one on-study EGD. A multivariable proportional hazard regression analysis was done to assess potential risk factors for ulcer development in the combined studies. Results: The REDUCE-1 and REDUCE-2 studies included a combined 1382 patients (HZT-501 N=930, ibuprofen N=452) in the primary analysis population. The life table estimate of the proportion of patients developing ulcers over 24 weeks was significantly lower with HZT-501 than ibuprofen (14.1% vs. 26.5%, p<0.0001). Multivariable risk factors are shown in the Table. Significant risk factors associated with development of ulcers were use of ibuprofen without concomitant famotidine therapy, prior ulcer and older age.Table: Multivariable analysis: risk of upper GI ulcersConclusion: Independent risk factors for the development of ulcers in NSAID users included use of NSAID without histamine-2 receptor antagonist therapy, history of ulcer disease and older age. Disclosure: L. Laine Consultant: Company 1, GlaxoSmithKline, 2, Takeda Pharmaceutical, 3, Horizon Therapeutics, 4, AstraZeneca, 5, Eisai, 6, Pozen, 7, Merck, 8, Pfizer Inc.; M.Schiff, Horizon Therapeutics, Consultant; M. Genovese, Horizon Therapeutics, Consultant; A. Kivitz, site investigator REDUCE-1; A.Bello, Horizon Therapeutics, Consultant; A. Grahn, Horizon Therapeutics, Employee; T. Walbert, Horizon Therapeutics, Employee; M. Weinblatt, Horizon Therapeutics, Consultant. This research was supported by an industry grant from Horizon Therapeutics, Inc.