AIMS: Non-vitamin K antagonist oral anticoagulants (NOACs) are displacing Vitamin K antagonists (VKAs) for stroke prophylaxis in patients with atrial fibrillation (AF). Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) could increase gastrointestinal bleeding (GIB) risks among these patients. The aim of this study was to examine the risk of GIB among Danish AF patients taking oral anticoagulants (OACs) and NSAID.

METHODS AND RESULTS: Using nationwide administrative registries, we determined concomitant NSAID use among anticoagulant-naïve patients with AF initiating OACs between August 2011 and June 2017. We calculated short-term absolute risks differences and hazard ratios (HRs) for GIB based on multiple adjusted cause-specific Cox regressions with time-dependent NSAID treatment.Among 41,183 patients (median age 70 years (IQR 64-78); 55% men), 21% of patients on NOACs and 18% on VKA were co-prescribed NSAIDs. The differences in absolute risk (95% Confidence Interval (CI)) of GIB within 14 days of commencing concomitant NSAID therapy (versus no concomitant NSAID therapy) were 0.10% (0.04%-0.18%) for NOACs and 0.13% (0.03%-0.24%) for VKA. NOACs overall were associated with less GIB than VKA (HR 0.77 [95% CI 0.69-0.85]). Compared with OACs alone, concomitant NSAIDs doubled the GIB risk associated with NOACs overall (HR 2.01 [95% CI 1.40-2.61] and with VKA (HR 1.95 [95% CI 1.21-2.69]).

CONCLUSION: Among this nationwide AF population taking OACs, concomitant NSAID therapy increased the short-term absolute risk of GIB. NOACs alone were associated with lower GIB risks than VKA but concomitant NSAIDs abolished this advantage. The findings align with post-hoc analyses from randomized studies. Physicians should exercise appropriate caution when prescribing NSAIDs for patients with AF taking NOACs or VKA.