| Summary: | Estimates of the effect of proton pump inhibitors (PPIs) on risks of upper and lower gastrointestinal bleeding (UGIB and LGIB) among low-dose aspirin users in routine clinical practice are variable (UGIB) or lacking (LGIB). We aimed to establish these risks in the same observational study population. Using UK primary care data, we followed 199,049 new users of low-dose aspirin (75–300 mg/day) and matched non-users at start of follow-up to identify incident UGIB/LGIB cases. In nested case–control analyses, adjusted odds ratios (ORs) were calculated for concomitant PPI use vs. past (discontinued) PPI use among current low-dose aspirin users. For UGIB (<i>n</i> = 987), ORs (95% CIs) were 0.69 (0.54–0.88) for >1 month PPI use and 2.65 (1.62–4.3) for ≤1 month PPI use. Among the latter group, ORs (95% CIs) were 3.05 (1.75–5.33) for PPI initiation after start of aspirin therapy, and 1.66 (0.63–4.36) for PPI initiation on/before start of aspirin therapy. For LGIB (<i>n</i> = 1428), ORs (95% CIs) were 0.98 (0.81–1.17) for >1 month PPI use and 1.12 (0.73–1.71) for ≤1 month PPI use. Among low-dose aspirin users, maintaining PPI use (>1 month) was associated with a significantly reduced UGIB risk. Neither short nor long-term PPI use affected LGIB risk.
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