Is it safe to take NSAIDs when using oral anticoagulants?

The use of oral anticoagulants (OACs) with NSAIDs results in clinical outcomes like those of OAC monotherapy, a study has shown.

“Approximately 4 percent of patients on OAC were also on NSAIDs, with clinical outcomes similar to OAC monotherapy,” the researchers said.

This multicentre registry-based cohort study was conducted at six anticoagulation clinics of the Michigan Anticoagulation Quality Improvement Initiative. The researchers included adults on OAC for venous thromboembolism or atrial fibrillation and used 4:1 propensity score matching to compare patients on OAC monotherapy to those on OAC plus NSAID therapy between 2011 and 2023.

Patients with a history of heart valve replacement, under 3 months of follow-up, or using two or more antiplatelet medications were excluded. Bleeding was the primary outcome, while other outcomes included bleeding subtypes, thrombosis/thromboembolism, healthcare utilization, and mortality.

A total of 12,083 patients were using OAC, of whom 449 (3.7 percent) were also prescribed NSAIDs. After propensity score matching, 1,796 patients on OAC monotherapy were compared to 449 patients on OAC plus NSAID. The two groups were well balanced and followed for an average of 30 months. [Am J Med 2025;138:1671-1679.E5]

Bleeding event rates per 100 patient-years were not significantly different between the OAC monotherapy and the OAC plus NSAID groups, including overall (25.1 vs 24.3; p=0.56), major, and nonmajor bleeding. Similar rates were also noted for thrombosis, emergency room visits, hospitalizations, transfusion, and mortality.

"[G]iven the limitations inherent to defining NSAID exposure, further studies are needed to evaluate if there is a ‘safe’ amount of NSAID use for patients on OAC,” the researchers said. “Additionally, better defining the role of gastroprotection in this setting should be a research priority.”

NSAID exposure

Both aspirin and nonaspirin NSAIDs inhibit cyclooxygenase, with nonselective NSAIDs competing for COX-1 binding. Nonaspirin NSAID use is associated with bleeding as well as an elevated risk of myocardial infarction and thrombosis, potentially due to decreases in the production of prostaglandin, according to the researchers.

Likewise, aspirin use could also increase the risk of bleeding. Nonaspirin NSAIDs appear to be less commonly prescribed to patients already on aspirin. [JAMA 2019;321:277-287; PLoS One 2016;11:e0160046]

Notably, the current study classified only nonaspirin NSAID use as NSAID exposure. 

“Given that including aspirin users in both groups could potentially bias our results towards the null hypothesis, we did a sensitivity analysis excluding aspirin users based on aspirin use at enrolment,” the researchers said. “This showed similar results.”

However, caution is needed when considering the use of NSAIDs for patients with a high cardiovascular risk profile and for those at increased risk for bleeding. [Nat Rev Cardiol 2020;17:574-584]

Although NSAIDs are increasingly being considered an alternative to opioids, patient risk profiles and potential adverse effects must be considered, according to the researchers. [Medicine (Baltimore) 2020;99:e20042]

“Overall, there is a need for randomized controlled trials to determine if there is a safe duration and/or dose of NSAIDs that can be administered with OACs for low bleeding risk patients,” the researchers said. “Until such data are available, patients should generally still avoid NSAIDs with OAC given the potential limitations with our observational study design.”