Co-administered oral anticoagulants with nonsteroidal anti-inflammatory drugs and the risk of bleeding: A systematic review and meta-analysis

Background: The bleeding risk of individuals taking nonsteroidal anti-inflammatory drugs (NSAIDs) concomitantly with oral anticoagulants (OACs) compared to OACs alone remains controversial. This meta-analysis aims to evaluate the bleeding risk of concomitant use of OACs and NSAIDs, and to make comparisons between different OACs types. Methods: PubMed, Embase, Cochrane Library and Web of Science were searched systematically until 11 August 2023 for studies reporting the bleeding risk of combined use of OACs and NSAIDs. Summary estimates with 95 % confidence interval (CI) were calculated by meta-analysis. Heterogeneity was assessed by I2 statistics. We performed subgroup analyses according to the types of NSAIDs, the types of OACs, the indication for therapy and the types of research. Results: A total of 27 studies were included. Taking vitamin K antagonist (VKAs) concurrently with NSAIDs was associated with a higher risk of any bleeding [odds ratio (OR) = 1.55; 95 % CI, 1.21 to 2.00; P = 0.0007), gastrointestinal bleeding (OR = 2.66; 95 % CI, 1.96 to 3.62; P < 0.00001) as well as major bleeding (OR = 1.55; 95 % CI, 1.04 to 2.30; P = 0.03). Concomitant exposure to direct OACs (DOACs) and NSAIDs increased the risks of any bleeding (OR = 1.54; 95 % CI, 1.33 to 1.80; P < 0.00001) and gastrointestinal bleeding (OR = 2.18; 95 % CI, 1.02 to 4.69; P = 0.05), but was nonsignificant for major bleeding (OR = 1.42; 95 % CI, 0.84 to 2.40; P = 0.19). Without considering other confounding factors, concomitant exposure to DOACs and NSAIDs was associated with a lower risk of bleeding compared to VKAs plus NSAIDs (OR = 0.55; 95 % CI, 0.34 to 0.90; P = 0.02) in atrial fibrillation and venous thromboembolism patients. Subgroup analyses showed that compared to VKAs only, concurrent administration of VKAs and nonselective NSAIDs was associated with a heightened risk of bleeding (OR = 3.06; 95%CI, 1.99 to 4.71; P < 0.00001). However, inconsistent result was observed when it comes to selective NSAIDs (OR = 1.99; 95%CI, 0.87 to 4.51; P = 0.10). Compared to DOACs only, combined use of rivaroxaban and NSAIDs increased bleeding risk (OR = 1.61; 95 % CI, 1.21 to 2.14; P = 0.001), while dabigatran co-administered with NSAIDs showed no significant association with bleeding (OR = 1.40; 95 % CI, 0.80 to 2.44; P = 0.24). Regardless of indication, concomitant administration of NSAIDs and DOACs increased the risk of bleeding. Conclusions: Co-administered OACs with NSAIDs significantly increased the risk of any bleeding and gastrointestinal bleeding compared to OACs alone. Without considering other confounding factors, DOACs were associated with a lower risk of bleeding compared to VKAs in atrial fibrillation and venous thromboembolism patients.