NSAID-induced Bleeding in AFib Patients Taking Oral Anticoagulants

Tuesday, October 2, 2018

R.L. Wynn

A recent study found the use of non-steroidal anti-inflammatory drugs (NSAIDs) in combination with oral anticoagulant therapy in patients with atrial fibrillation was associated with an increased risk of major bleeding compared with patients who did not use NSAIDs.

This was a conclusion from a study out of Yale New Haven Health which analyzed data from a previous published study known as the RE-LY trial. It specifically examined aFib patients taking dabigatran (Pradaxa) 110 mg or 150 mg twice daily or warfarin.

Transient or prolonged use of NSAIDs occurs for a variety of reasons, including the management of osteoarthritis and rheumatoid arthritis. Many of these patients are also taking oral anticoagulant drugs, such as dabigatran, for cardiovascular problems. The combination of NSAIDs with oral anticoagulants poses serious risk of bleeding.

The objectives of this study by Kent, et al, was to assess the effects of the combined use of NSAIDs with oral anticoagulant therapy, specifically dabigatran or warfarin, in the context of patients with atrial fibrillation to quantify bleeding and thrombotic risks. The study can be accessed at: Kent, et al. “Concomitant oral anticoagulant and nonsteroidal anti-inflammatory drug therapy in patients with atrial fibrillation.” J Am Coll Cardiol 2018; 72(3): 255-67; from the Department of Internal Medicine, Bridgeport Hospital, Yale New Have Health, Bridgeport, Connecticut.

Study Methods

The 2018 Kent study was based on data from the 2009 RE-LY trial by Ezekowitz, MD. RE-LY is the acronym for Randomized Evaluation of Long Term Anticoagulant Therapy Trial. 

The RE-LY trial was a prospective evaluation of dabigatran 150 mg or 110 mg twice daily in comparison to warfarin among 18,113 patients with atrial fibrillation. The Kent study analyzed the RE-LY trial and compared the group of patients who used nonselective NSAIDs at least once during the RE-LY trial (n=2,279) with patients who never used NSAIDs during the trial (n=15,834). Baseline characteristics and outcomes of patients were described according to NSAID use versus no NSAID use. Analysis of NSAID use excluded aspirin and selective COX-2 inhibitors.

Clinical outcomes focused on major bleeding, as defined (from the RE-LY trial) as follows:

  • Major bleeding was greater or equal to one of the following criteria:
    • Bleeding associated with reduction in hemoglobin level of at least 2.0 g/l
    • Bleeding leading to transfusion of at least 2 units of blood or packed cells
    • Symptomatic bleeding in a critical area or organ such as intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding
  • Minor bleeds were defined as clinical bleeds that do not fulfill the criteria of major bleeds

Study Results

Out of 18,113 total patients randomized in the RE-LY trial to either dabigatran or warfarin:

  • 2,279 patients (12.6%) used NSAIDs at least once during the study period
  • 13% of NSAID users took dabigatran 110 mg twice daily
  • 11.9% of NSAID users took dabigatran 150 mg twice daily
  • 12.8% of NSAID users took warfarin

The annualized rate of major bleeding when NSAIDs were used at least once in combination with anticoagulant therapy was significantly elevated to 1.39 greater bleeding risks compared with patients who did not use NSAIDs:

  • The rates of major bleeding for each anticoagulant treatment arm (dabigatran 110 mg; dabigatran 150 mg; warfarin) were elevated with NSAID use
  • Major bleeding rates with dabigatran 110 mg and 150 mg twice daily were not altered relative to warfarin with NSAID use
  • Gastrointestinal major bleeding was elevated across all anticoagulant treatment arms with NSAID use
  • NSAID use did not alter the rate of gastrointestinal major bleeding with dabigatran 110 mg and 150 mg twice daily relative to warfarin
  • Stroke/systemic embolism was significantly elevated among patients taking NSAIDs in combination with anticoagulant therapy
  • Ischemic stroke and hospitalizations were more frequent with NSAID use compared with patients who did not take NSAIDs


This study was the first to evaluate NSAID use with dabigatran in atrial fibrillation patients. The rates of major bleeding, GI major bleeding, stroke/systemic embolism, ischemic stroke, and hospitalization with oral anticoagulant therapy were significantly elevated compared with patients who did not use NSAIDs.  Hospitalization was common (approximately 20% per year among a patient population with atrial fibrillation on anticoagulants without NSAID use) and was significantly elevated with NSAID use (approximately 29% per year).

Non-GI bleeding represented 60% and GI bleeding represented 40% of major bleeding events among the NSAID group.

The present analysis did not include the COX-2 inhibitor celecoxib due to a small sample size. But the cardiovascular risk associated with COX-2 inhibitors does not necessarily make them a safe alternative to nonselective NSAIDs.

Study Limitations

  1. There was no information on the specific NSAID patients were taking, the doses, or durations of exposure.
  2. Patients in the RE-LY study were allowed to stop and start NSAIDs periodically.
  3. Baseline characteristics data did not capture the prevalence of osteoarthritis, rheumatoid arthritis, or other inflammatory conditions to explain the use of NSAIDs.

Kent Study Conclusions

The use of NSAIDs in combination with oral anticoagulant therapy, specifically dabigatran 110 mg or 150 mg twice daily or warfarin, in patients with atrial fibrillation was associated with a higher risk of major bleeding, thromboembolism, and hospitalization compared with patients who did not use NSAIDs. 

Published Editorial

An editorial on the Kent study titled “Are the NSAIDs double trouble?” by Sam Schulman and James Aisenberg appeared in the Journal of the American College of Cardiology. It noted that NSAIDs have been considered the default option for many osteoarthritic patients and their use has increased over time. Growing numbers of individuals with both osteoarthritis and atrial fibrillation currently consume NSAIDs and some oral antiplatelet or anticoagulant.

Results from the Kent et al study showed that NSAIDs were associated with they termed “double trouble”: The increased risk of major GI bleeding and the increased risk of non-GI major bleeds in patients with atrial fibrillation and taking dabigatran or warfarin. On the other hand, the risk of intracranial hemorrhage and myocardial infarction were not increased by NSAIDs.

NSAID-related bleeding could be related to inhibition of platelet function, which can both induce and prolong bleeding, and to tissue injury, mostly at the level of the GI mucosa. The editorial went on to suggest how to manage patients with atrial fibrillation and osteoarthritis. For pain control, NSAID use should be moderated when appropriate and a COX-2 inhibitor, such as celecoxib, should be considered. In addition, a gastroprotective agent, usually a proton-pump inhibitor should be usually co-prescribed with an NSAID.  It has been suggested that this strategy could reduce the risk of GI bleeding.

Richard L. Wynn, BS Pharm, PhD, is professor of pharmacology at the Baltimore College of Dental Surgery, Dental School, University of Maryland Baltimore.

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