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

Abstract

BackgroundThe 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. MethodsPubMed, 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. ResultsA 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. ConclusionsCo-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.