Selective NSAIDs reduce risk of GI bleeding, study suggests

Selective non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal (GI) bleeding when used with direct-acting oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF), according to the results of a study.

Publishing their findings in JAMA Network Open: Cardiology on 26 May 2026, researchers analysed data from 30,240 patients with NVAF, using electronic medical records in the UK and claims data in Canada, between 2011 and 2020. Of the cohort, more than one-third of participants (43.3%, 13,094) were female and more than half (56.7%, 17,146) were male.

When COX-2–selective NSAIDs were used with DOACs, there was a 37% decrease in the risk of GI bleeding compared with the use of nonselective NSAIDs with DOACs, the study results revealed.

The study authors said the finding is “important given the high baseline risk of GI bleeding during treatment with DOACs”.

NSAIDs have been associated with increased risk of GI bleeding, but the results of a study published in 2000 showed that COX-2–selective NSAIDs have been observed to be less likely to cause this compared with non-selective NSAIDs when prescribed to patients with rheumatoid arthritis or osteoarthritis.

In the UK, the study authors found that diclofenac (Voltarol; Haleon) was the most commonly prescribed COX-2–selective NSAID (39.9%), while naproxen was the most commonly prescribed non-selective NSAID (65.1%). In Quebec, Canada, celecoxib (Celebrex; Pfizer) was most common COX-2–selective NSAID (85.6%), while naproxen was also the most common non-selective NSAID (78.2%).

The study authors also noted that their study is the first to look specifically at the role of COX-2 selectivity in NSAIDs and the risk of GI bleeding among patients with NVAF treated with DOACs. 

Paul Wright, consultant cardiovascular pharmacist at Barts Health NHS Trust in London, said: “[It was an] interesting study, and as predicted by the bleeding risk of the baseline NSAIDs, there was a reduction seen in those given a COX-2 selective agent over a non-selective NSAID.”

However, he added: “In this observational study, those that are deemed high bleeding risk are likely to be excluded and the use of alternative agents given. Diclofenac, whilst it has a preference for COX-2, is usually considered a non-selective NSAID, ergo the effects may be further enhanced for COX-2.”

Wright also noted that the choice of NSAID is based on bleeding risk and other factors, while the choice of DOAC also has an impact on gastrointestinal bleeding versus warfarin.

“[NSAIDs] should be used in caution with DOACs, given high baseline risks when starting DOACs: advice from the SPS [Specialist Pharmacy Service] and BNF [British National Formulary] should be followed, alongside reviewing the need for the NSAID and avoiding chronic use.”

“If an alternative analgesic cannot be used and an NSAID is indicated, prescribe the lowest effective dose for the shortest possible duration,” he said.

“This study suggests that if there are no contraindications or other comorbidities, a COX-2 selective NSAID could be considered due to reduced bleeding risk over a non-selective NSAID. Further detail is required to consider any wider impact, including cardiovascular outcomes, before we could strongly recommend.”