Multinational cohort study (UK EHR + Quebec claims, 2011-2020) in 30,240 patients with nonvalvular atrial fibrillation initiating concomitant DOAC and NSAID (37,833 episodes; 45.2% COX-2-selective, 54.8% nonselective). Mean age 72.1 years, 56.7% male. Pooled weighted analysis with inverse-probability-of-treatment weighting showed that COX-2-selective NSAIDs combined with DOACs were associated with fewer gastrointestinal bleeds (HR 0.63; 95% CI 0.46-0.87; I²=56%) and fewer non-GI bleeds (HR 0.54; 95% CI 0.40-0.74; I²=0%) versus nonselective NSAIDs. The effect was stronger in women (HR 0.50 for GI bleeding) than in men (HR 0.85). No major effect modification by age, order of initiation, baseline bleeding risk, or specific DOAC. COX-2-selective NSAIDs thus retain their GI-protective benefit during DOAC therapy; future research should clarify the relationship with stroke risk.
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. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURES: Concomitant use of DOACs and COX-2-selective NSAIDs or concomitant use of DOACs and nonselective NSAIDs. MAIN OUTCOMES AND MEASURES: 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.
