Patients with atrial fibrillation (AF) receiving antithrombotic treatment are at increased risk for bleeding if they also take a nonsteroidal anti-inflammatory drug (NSAID), even for a short period, a new nationwide Danish study has found.

The data suggest that a serious bleeding event occurs in up to 1 in 400 to 500 patients with AF exposed to an NSAID for 2 weeks and that the risk is elevated with both selective cyclooxygenase (COX)-2 inhibitors and nonselective NSAIDs.

The findings are important because NSAIDs are so widely available and commonly used, commented lead study author Morten Lamberts, MD, PhD, Department of Cardiology, Gentofte University Hospital, Hellerup, Denmark.

“Any safety issues are a major public health concern,” said Dr Lamberts. “Patients should know that it’s possible that even over-the-counter drugs might put them at increased bleeding and thromboembolic risk.”

The study is published in the November 18 issue of Annals of Internal Medicine.
The researchers used data from the Denmark’s National Patient Registry, which contains information on hospitalizations and on dosage, strength, and date of dispensed prescription drugs. The analysis included 150,900 patients, median age 75 years, who were hospitalized with a first-time diagnosis of AF between 1997 and 2011. During a median follow-up of 6.2 years, 35.6% of patients were prescribed an NSAID.

Dr Morten Lamberts
Study participants had a mean HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score of 1.5 and mean CHA2DS2VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, sex) score of 2.8. Approximately 70% were being treated with an antiplatelet or oral anticoagulant.

Investigators categorized rofecoxib and celecoxib as selective COX-2 inhibitors and ibuprofen, diclofenac, and naproxen as nonselective NSAIDs. Since 2001, ibuprofen has been the only NSAID available in Denmark without a prescription, but only in low doses and in limited quantities. Since that time, this agent has accounted for 15% to 20% of all NSAID sales.

The study showed that serious bleeding events, including intracranial and gastrointestinal bleeding, occurred in 11.4% of the patients and thromboembolic events in 13.0%. The absolute risk for serious bleeding with 14 days of continuous NSAID exposure was 3.5 events per 1000 patients vs 1.5 events per 1000 patients without NSAID exposure, with an absolute risk difference of 1.9 events per 1000 patients. In patients selected for oral anticoagulant therapy, the absolute risk difference was 2.5 events per 1000 patients.

“This suggests a serious bleeding event in 1 of 400 to 500 patients exposed to an NSAID for 14 days,” the authors write.
The increased absolute risk for serious bleeding and thromboembolism existed across all antithrombotic regimens, for example single-antiplatelet therapy with either aspirin or clopidogrel, monotherapy with oral anticoagulants, or dual therapy with an oral anticoagulant and a single antiplatelet.
The study showed that the risk for serious bleeding with NSAID treatment was doubled compared with no NSAID treatment. The risk for thromboembolism was also increased.

Endpoint Hazard Ratio (95% Confidence Interval)

Serious bleeding 2.27 (2.14 – 2.40)
Thromboembolism 1.36 (1.27 – 1.45)

While all types of NSAIDs were associated with increased risk, diclofenac, naproxen, and rofecoxib (this last one is no longer marketed, according to Dr Lamberts) showed a particularly increased risk. For example, for diclofenac the hazard ratio for serious bleeding was 3.08 (95% confidence interval, 2.77 – 3.43).

The fact that the risk for serious bleeding occurred even within 2 weeks “is particularly worrisome as this suggests no safe therapeutic window,” said Dr Lamberts.

When researchers restricted the analysis to the years when over-the-counter NSAIDs weren’t available (1997 to 2001), the results for bleeding risk were similar. “Having nonregistered ibuprofen users potentially diluted into the larger non-NSAID group, one could speculate if the difference might be even larger than what we found,” said Dr Lamberts.

The risk for death after a nonfatal episode of serious bleeding during NSAID treatment was also increased, the study found. In addition, a high NSAID dose was associated with incremental risk for bleeding, suggesting a dose-response relationship.

Many patients with AF take NSAIDs to relieve pain. “I believe many individuals self-treat pain with NSAIDs because they’re available and accessible,” said Dr Lamberts.

The study results support previous recommendations that NSAIDs be discouraged unless other possibilities, such as physical therapy, acetaminophen, or alternative analgesics, have been exhausted.

Because non–vitamin K antagonist oral anticoagulants have a similar or better overall bleeding risk profile compared with warfarin, physicians might consider switching to one of those agents in patients needing NSAIDs, said the authors.