OBJECTIVES Minimizing the risk of upper gastrointestinal (GI) adverse events (AEs), which may compromise patient compliance with low-dose acetylsalicylic acid (LDASA) therapy, is an important part of cardiovascular (CV) risk management. Using data from the AstraZeneca ARIADNE database we assessed the risk of upper GI AEs (including peptic ulcer disease, esophagitis and dyspepsia) and the benefits of acid-suppressive therapy with proton pump inhibitors (PPIs) in patients taking LDASA for CV risk management. METHODS The ARIADNE database was created by Astra (now AstraZeneca) to store safety-related clinical study data. For this analysis, data on elderly patients with mild hypertension were extracted. During the follow-up period (mean 3.7y), patients received antihypertensive therapy (hydrochlorothiazide, plus an angiotensin II receptor antagonist or placebo) and other treatments required for their individual care. Among patients without a history of upper GI AEs (n=4539), Cox proportional hazard models were used to estimate the relative risk (RR; adjusted for age, sex, and body mass index) of upper GI AEs associated with concomitant use of LDASA and in relation to when PPI therapy was commenced. RESULTS Overall, 1191 patients (26.2%) received LDASA during the study (with or without concomitant acid-suppressive therapy). There was a trend towards an increased risk of upper GI AEs in current LDASA users (RR, 1.27; 95% confidence interval [CI]: 0.95, 1.71). Within the subgroup using LDASA and PPIs (n=138, 11.6%) the RR of upper GI AEs was 5.41 (95% CI: 3.43, 8.53) when LDASA therapy was initiated before the start of PPI therapy. Adding LDASA to an existing PPI treatment protected against an increased risk of GI AEs. CONCLUSIONS These data suggest that the risk of upper GI AEs is high in elderly patients receiving LDASA for CV risk management, and that PPIs confer a protective effect against upper GI AEs in these at-risk individuals.