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Concurrent use of both medications puts patients at a significant risk of bleeding that warrants appropriate management strategies

Algorithm

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.

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.(

Misoprostol also has been demonstrated to help prevent gastric ulcer in those who receive NSAIDs.

Therefore, alternate management strategies such as utilizing proton pump inhibitors or misoprostol may help reduce bleeding events.

Thus, avoiding and/or limiting the use of NSAIDs is an ideal strategy to prevent serious complication from these medications.

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

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.

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.

Concomitant NSAIDs occur with 24.3% of warfarin courses of therapy

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