Rationale

Approximately 2 million patients in North America are on warfarin long-term. Of those patients, 15-30% also have the musculoskeletal disease and may benefit from Nonsteroidal anti-inflammatory drugs (NSAIDs) treatment.(1) Concomitant NSAIDs occur with 24.3% of warfarin courses of therapy.(2) The effectiveness of warfarin in preventing and reducing the occurrence of thromboembolic events is widely established.(3, 4) It is well known that NSAIDs can inflict damage to gastric and duodenal mucosa, which significantly contribute to gastrointestinal bleeding, morbidity, and mortality.(5-9) Concurrent use of both medications puts patients at a significant risk of bleeding that warrants appropriate management strategies.

Algorithm

Explanation

Warfarin is a vitamin K antagonist, which competitively inhibits a series of coagulation factors, as well as proteins C and S. These factors are biologically activated by the addition of carboxyl groups depending on vitamin K. Warfarin competitively inhibits this chemical reaction, thus depleting functional vitamin K reserves and hence reducing the synthesis of active coagulation factors.(10)

Non-selective NSAIDs inhibit cyclooxygenase (COX) enzymes, COX-1 and COX-2 at different extent, leading varying effects on bleeding.(11, 12) COX-1 catalyzes the initial step in the formation of thromboxane (TxA2), and prostaglandins.(11, 12) TxA2 stimulates platelet aggregation.(13) Prostaglandins protect the gastrointestinal tract by increasing mucosal blood flow and the thickness of mucus layer,  stimulating bicarbonate secretion, and reducing gastric acid secretion.(14) COX-2 is predominantly a cytokine-induced enzyme produces prostaglandins that promote pain and inflammation.(15) Thus, inhibitors of COX-2 are believed to have lower risk of bleeding.(1, 16, 17) The American College of Rheumatology recommends that patients taking warfarin to take a COX-2 inhibitor instead of an NSAID if they need NSAID therapy.(16) However, there is some evidence suggesting that COX-2 inhibitors might not be a safer options in patients on warfarin.(18, 19) Moreover, another study reported that a patient who experienced extensive bleeding after introduction of celecoxib was a heterozygote with CYP2C9 *2 and *3 alleles, which were associated with low metabolism.(20) These results suggest that pharmacogenetic testing may be useful to refine the risk group for NSAID-warfarin interaction.(20)

Bleeding is a common side effect of NSAIDs and warfarin. The mortality rate for patients who are hospitalized for NSAID-related upper gastrointestinal bleeding is 5% to 10%.(21) The use of NSAID alone increases the risk for hemorrhagic UGIB 4 fold, whereas warfarin alone increases the risk by 4.3 times compare to placebo.(16) Concurrent use of warfarin and NSAIDs increase the risk of GI bleeding,(16-18, 22-25) and general bleeding events.(16, 25-28) A retrospective case-control study showed that initiating NSAIDs in warfarin users could increase INR in 39.8% of the patients.(29) Moreover, the relative risk of upper GI bleeding with concurrent warfarin and NSAID use is 2.9 to 3.3 higher than compared to a patient who takes warfarin alone.(16) Concurrent use of meloxicam and warfarin-interacting medications with maintenance doses of warfarin >40 mg/week was more susceptible to INR increase when a NSAID was added.(29)

While patients on warfarin are prone to bleeding from any source, it most frequently occurs from the gastrointestinal tract. Thus, avoiding and/or limiting the use of NSAIDs is an ideal strategy to prevent serious complication from these medications. However, limiting the chronic use of NSAIDs is challenging because they are one of the most commonly used medications worldwide due to their effectiveness as analgesics, antipyretics, and anti-inflammatory agents. Therefore, alternate management strategies such as utilizing proton pump inhibitors or misoprostol may help reduce bleeding events. Proton-pump inhibitors (PPIs) has been shown to effectively heal gastroduodenal ulcers among NSAIDs users,(30) and prevent NSAID-related gastroduodenal mucosal injury.(31) A large population-based study showed that  using PPIs to prevent upper gastrointestinal bleeding in patients receiving warfarin associated with lowering the incidence of hospitalization(32). Another case-control study demonstrated that PPIs reduced the risk of upper gastrointestinal bleeding in patients taking NSAIDs and also provided a significant advantage for patients taking warfarin and NSAIDs concomitantly(33). Misoprostol also has been demonstrated to help prevent gastric ulcer in those who receive NSAIDs.(34-36)

Precautions

Please note that this algorithm does not include other risk factors that may contribute to bleeding risk in these patients

  • The VKORC1 and CYP2C9 genotypes are the most important known genetic determinants of warfarin dosing. Warfarin targets VKORC1, an enzyme involved in vitamin K recycling. The variants CYP2C9*2 and *3, required with a lower dose of warfarin. The FDA-approved drug label for warfarin states that CYP2C9 and VKORC1 genotype information, when available, can assist in the selection of the initial dose of warfarin.(37)
  • Several risk factors for NSAID-related gastroduodenal bleeding are old age, a history of peptic ulcer disease, high dosages of NSAIDs, concomitant use of different NSAIDs. (9, 16)
  • Both corticosteroids and aldosterone antagonists have been shown to substantially increase the risk of upper gastrointestinal bleeding in patients on NSAIDs, with relative risks of 12.8 and 11 respectively compared to a risk of 4.3 with NSAIDs alone.(38)

Artifacts for implementers

Drug interaction algorithm implementation survey

Supporting documentation

Webinar on 03/11/20

Warfarin-NSAIDs

References

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