Direct Oral Anticoagulants, COX-2-Selective NSAIDs, and Gastrointestinal Bleeding in Atrial Fibrillation

It is unclear whether the beneficial effects of nonsteroidal anti-inflammatory drugs (NSAIDs) that selectively inhibit cyclooxygenase 2 (COX-2) in decreasing the risk of gastrointestinal (GI) bleeding are retained in patients with nonvalvular atrial fibrillation (NVAF) concomitantly treated with direct oral anticoagulants (DOACs).

To assess whether concomitant use of DOACs and COX-2-selective NSAIDs is associated with a decreased risk of GI bleeding vs concomitant use of DOACs and nonselective NSAIDs in patients with NVAF.

This multinational cohort study used electronic medical records from the UK and claims data from Quebec between January 1, 2011, and December 12, 2020. Adult patients (aged ≥18 years) with NVAF who initiated concomitant use of DOACs and NSAIDs during the study period were included. Cohort entry was the first day of concomitant use. Patient data were followed until a study outcome, death, or treatment discontinuation or switch. All analyses were conducted between November 19, 2024, and July 25, 2025.

Concomitant use of DOACs and COX-2-selective NSAIDs or concomitant use of DOACs and nonselective NSAIDs.

The primary outcome was GI bleeding, and the secondary outcome was non-GI bleeding. Inverse probability of treatment weighting was used to control for confounding. Cox models were used to estimate site-specific hazard ratios (HRs) and 95% CIs, which were pooled using random-effects models. Further stratification was performed for potential effect modifiers.

The study cohort included 30 240 patients with NVAF who initiated concomitant use of DOACs and NSAIDs (mean [SD] age, 72.1 [9.2] years, 17 146 male [56.7%]). They contributed 37 833 episodes of concomitant use of DOACs and NSAIDs (45.2% COX-2-selective NSAIDs, 54.8% nonselective NSAIDs). Concomitant use of DOACs and COX-2-selective NSAIDs was associated with a decreased risk of GI bleeding (pooled weighted HR, 0.63 [95% CI, 0.46-0.87]; I2 = 56%) and non-GI bleeding (pooled weighted HR, 0.54 [95% CI, 0.40-0.74]; I2 = 0%) vs concomitant use of DOACs and nonselective NSAIDs. Female patients had a greater decreased risk of GI bleeding associated with concomitant use of DOACs and COX-2-selective NSAIDs (pooled weighted HR, 0.50 [95% CI, 0.31-0.80]; I2 = 0%) than male patients (HR, 0.85 [95% CI, 0.55-1.32]; I2 = 78%). There was no major effect measure modification by age, order of drug initiation in concomitant use, baseline bleeding risk, or individual DOACs.

These findings suggest that COX-2-selective NSAIDs may retain their beneficial effects regarding GI bleeding during concomitant use with DOACs. Future studies should examine the association of COX-2 selectivity with stroke risk among patients treated with DOACs.