Venous thromboembolism (VTE) patients on anticoagulation therapy often present with pain and inflammation amenable to nonsteroidal anti-inflammatory drugs (NSAIDs), but the decision regarding their use can be contentious given increased bleeding risk. NSAIDs are widely prescribed for their analgesic, anti-pyretic, and anti-inflammatory effects by inhibiting the cyclo-oxygenase (COX-1, COX-2) enzymes. This alters the arachidonic acid pathway metabolites including prostaglandins (causes pain and inflammation), prostacyclins (promotes vasodilation and inhibits platelet aggregation), and thromboxanes (causes platelet aggregation).1 Upsetting this pathway can increase bleeding risk by causing gastrointestinal tract toxicity and disrupting platelet function.2 The development of selective COX-2 inhibitors was aimed to ameliorate this by maintaining prostaglandins levels, but resulted in increased cardiovascular events for some patients.1,2
The evidence to date on NSAIDs with oral anticoagulants is conflicting with some studies showing increased bleeding risk,3, 4, 5 whereas others show no significant difference.6,7 Until recently, much of this information revolved around vitamin K antagonists (VKAs) with little data to guide practice decisions for direct oral anticoagulants (DOACs). A 2023 systematic review of 27 studies representing >1.1 million patients concluded that NSAIDs increased all bleed risk with odds ratio of 1.5 for DOACs and 2.2 for VKAs, respectively.8 However, there was marked heterogeneity of the included studies and the vast majority of these were designed to investigate other primary objectives.
Thus, to better elucidate the effects of NSAIDs in VTE patients on anticoagulation, Petersen et al9 completed an elegant cohort study using the Danish National Health Service registry. The registry included 51,794 patients initiated on oral anticoagulants (37,991 on DOACs, 13,789 on VKAs) for VTE between 2012 and 2022 with information on NSAID use and bleeding. Adjusted hazard ratio for combined NSAID use was 2.09. Among the NSAIDs investigated, ibuprofen had the lowest adjusted hazard ratio of 1.79 compared with 3.30 for diclofenac and 4.10 for naproxen. DOACs combined with NSAIDs showed a higher adjusted hazard ratio of 2.27 compared with that of 1.79 for VKAs. Adjusted hazard ratios for rivaroxaban and apixaban were nearly identical, while data were inconclusive for dabigatran and edoxaban due to their limited use. Notably, the adjusted hazard ratios with NSAID use was elevated not just for gastrointestinal bleeding at 2.24, but also for all bleeding, including intracranial (3.22), thoracic and respiratory tract (1.36), urinary tract (1.57), and anemia (2.99). Overall, the results showed that concurrent NSAID use slightly increased bleed risk for both DOACs and VKAs.9
These results are consistent with previous findings showing that adding NSAIDs to oral anticoagulants can increase bleed risk.8,10,11 This finding aligns with our pathophysiological understanding of the effects of NSAIDs, and this study reminds us to use NSAIDs with caution and that ibuprofen may be the preferred choice when needed at the minimal effective dose as risk is dose-dependent.12 Although concomitant proton pump inhibitor use may be protective, it is important to recognize that bleed risk is not limited to the gastrointestinal tract. Additional research on specific DOAC and NSAID combinations regarding safety may be beneficial for guiding therapy choices.
Funding
None.
Disclosures
None.
Footnotes
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest.
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