NSAIDs May Be Safe for Use in Hemophilia, but More Research Is Needed

In patients with hemophilia, prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) is typically avoided due to a fear of adverse bleeding or cardiovascular events. A review published in Blood Reviews found that most reports on NSAIDs and safety in patients with hemophilia did not demonstrate a risk of adverse bleeding or cardiovascular events.

Hemophilia is a rare inherited disorder characterized by a deficiency in clotting factor VIII in hemophilia A or factor IX in hemophilia B. Both types of hemophilia can lead to recurrent bleeding incidents involving the joints and muscles, some of which can be life threatening. Joint damage known as hemophilic arthropathy often occurs due to repeated joint bleeds, even in patients on prophylactic treatment whose bleeds are subclinical.

In rheumatic diseases such as osteoarthritis or rheumatoid arthritis, NSAIDs are mainstays for managing chronic joint pain and inflammation. NSAIDs, which can be selective or nonselective, are effective for pain relief, easily accessible, and inexpensive. Plus, they can be a safer alternative to opioids for individuals with chronic pain. In recent years, opioid poisoning in patients and opioid-related overdoses in the general public have become increasingly common in certain countries, including the United States.

NSAIDs may also have potential to modify the course of hemophilic arthropathy based on impact on other conditions. For example, celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, has shown benefits for osteoarthritis in vitro without affecting healthy cartilage. The anti-inflammatory function of NSAIDs might also protect cartilage. However, there are concerns over potential risks of vascular events with both selective and nonselective NSAID treatment as well as bleeding events in patients with hemophilia.

While older, nonselective drugs are known to have antiplatelet and gastrointestinal adverse effects, selective NSAIDs are a different story. Still, their prescription is often restrained by concerned providers.

“With the introduction of selective inhibitors, the use of NSAIDs in patients with bleeding disorders becomes an attractive option, especially if reduction of pain is accompanied by cartilage protection, as seen in other rheumatic diseases,” the authors wrote.

Nineteen articles were included in the review: 7 reported on clinical outcomes, 8 reported on laboratory outcomes, and 4 covered laboratory and clinical outcomes. The review included selective and nonselective NSAIDs, including COX inhibitors.

Regarding selective COX-2 inhibitors, none of the studies in the review reported thrombotic cardiovascular events with their use. The COX-2 inhibitor celecoxib showed no increase in bleeding risk, but rofecoxib resulted in 2 small bleeding events. Although not statistically significant, trends toward reduced upper gastrointestinal bleeding were seen with recent celecoxib or rofecoxib use in the review.

Most studies did not show statistically significant differences in hemorrhages in patients on traditional, nonselective NSAIDs vs a placebo. While one small study found an increased bleeding risk with traditional NSAID use, the findings were not statistically significant. Once adjusted for age, liver decompensation, and platelet count, there was no longer a risk specifically associated with NSAID use. Laboratory studies mostly found no significant differences between bleeding time, platelet aggregation, or transfusion requirement in patients on traditional NSAIDs vs a placebo.

While the hesitation to prescribe NSAIDs to patients who have hemophilia is not supported by current research based on the review, the studies had significant limitations. Older studies that were of lower quality and had a high risk of bias were included in an effort to provide a complete overview of the landscape; study designs and populations differed significantly. There was also a lack of information on hemophilia severity and prophylactic adherence in some cases. In future studies, longer follow-up would also help provide more definitive insight.

Reference

van Bergen EDP, Monnikhof M, Lafeber FPJG, Schutgens REG, Mastbergen SC, van Vulpen LFD. The fear for adverse bleeding and cardiovascular events in hemophilia patients using (non-)selective non-steroidal anti-inflammatory drugs: A systematic review reporting on safety. Blood Rev. Published online June 24, 2022. doi:10.1016/j.blre.2022.100987