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.



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)


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

Supporting documentation


  1. Dentali F, Douketis J, Woods K, Thabane L, Foster G, Holbrook A, et al. Does Celecoxib Potentiate the Anticoagulant Effect of Warfarin? A Randomized, Double-Blind, Controlled Trial. The Annals of pharmacotherapy. 2006;40:1241-7.
  2. Malone DC, Hutchins DS, Haupert H, Hansten P, Duncan B, Van Bergen RC, et al. Assessment of potential drug-drug interactions with a prescription claims database. Am J Health Syst Pharm. 2005;62(19):1983-91.
  3. Heneghan C, Alonso-Coello P, Garcia-Alamino JM, Perera R, Meats E, Glasziou P. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet. 2006;367(9508):404-11.
  4. Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, et al. Guidelines on oral anticoagulation with warfarin – fourth edition. Br J Haematol. 2011;154(3):311-24.
  5. Lanas A, Perez-Aisa MA, Feu F, Ponce J, Saperas E, Santolaria S, et al. A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use. Am J Gastroenterol. 2005;100(8):1685-93.
  6. Sostres C, Gargallo CJ, Lanas A. Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage. Arthritis Res Ther. 2013;15 Suppl 3:S3.
  7. Matsui H, Shimokawa O, Kaneko T, Nagano Y, Rai K, Hyodo I. The pathophysiology of non-steroidal anti-inflammatory drug (NSAID)-induced mucosal injuries in stomach and small intestine. J Clin Biochem Nutr. 2011;48(2):107-11.
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  15. Karim A, Tolbert D, Piergies A, Hubbard RC, Harper K, Wallemark CB, et al. Celecoxib does not significantly alter the pharmacokinetics or hypoprothrombinemic effect of warfarin in healthy subjects. J Clin Pharmacol. 2000;40(6):655-63.
  16. Chung L, Chakravarty EF, Kearns P, Wang C, Bush TM. Bleeding complications in patients on celecoxib and warfarin. J Clin Pharm Ther. 2005;30(5):471-7.
  17. Cheetham TC, Levy G, Niu F, Bixler F. Gastrointestinal safety of nonsteroidal antiinflammatory drugs and selective cyclooxygenase-2 inhibitors in patients on warfarin. Ann Pharmacother. 2009;43(11):1765-73.
  18. Battistella M, Mamdami MM, Juurlink DN, Rabeneck L, Laupacis A. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med. 2005;165(2):189-92.
  19. Mamdani M, Juurlink DN, Kopp A, Naglie G, Austin PC, Laupacis A. Gastrointestinal bleeding after the introduction of COX 2 inhibitors: ecological study. Bmj. 2004;328(7453):1415-6.
  20. Malhi H, Atac B, Daly AK, Gupta S. Warfarin and celecoxib interaction in the setting of cytochrome P450 (CYP2C9) polymorphism with bleeding complication. Postgrad Med J. 2004;80(940):107-9.
  21. Choi KH, Kim AJ, Son IJ, Kim KH, Kim KB, Ahn H, et al. Risk factors of drug interaction between warfarin and nonsteroidal anti-inflammatory drugs in practical setting. J Korean Med Sci. 2010;25(3):337-41.
  22. Ravic M, Johnston A, Turner P, Ferber HP. A study of the interaction between lornoxicam and warfarin in healthy volunteers. Hum Exp Toxicol. 1990;9(6):413-4.
  23. Dean L. Warfarin Therapy and VKORC1 and CYP Genotype. In: Pratt V, McLeod H, Rubinstein W, Dean L, Kattman B, Malheiro A, editors. Medical Genetics Summaries. Bethesda (MD): National Center for Biotechnology Information (US); 2012.
  24. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal Toxicity of Nonsteroidal Antiinflammatory Drugs. New England Journal of Medicine. 1999;340(24):1888-99.
  25. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at high risk for hemorrhagic peptic ulcer disease. Arch Intern Med. 1993;153(14):1665-70.
  26. Johnsen SP, Sorensen HT, Mellemkjoer L, Blot WJ, Nielsen GL, McLaughlin JK, et al. Hospitalisation for upper gastrointestinal bleeding associated with use of oral anticoagulants. Thromb Haemost. 2001;86(2):563-8.
  27. Schelleman H, Brensinger CM, Bilker WB, Hennessy S. Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. PLoS One. 2011;6(6):e21447.
  28. Mosholder AD, Racoosin JA, Young S, Wernecke M, Shoaibi A, MaCurdy TE, et al. Bleeding events following concurrent use of warfarin and oseltamivir by Medicare beneficiaries. Ann Pharmacother. 2013;47(11):1420-8.
  29. Zhang K, Young C, Berger J. Administrative claims analysis of the relationship between warfarin use and risk of hemorrhage including drug-drug and drug-disease interactions. J Manag Care Pharm. 2006;12(8):640-8.
  30. Vitry AI, Roughead EE, Ramsay EN, Preiss AK, Ryan P, Gilbert AL, et al. Major bleeding risk associated with warfarin and co-medications in the elderly population. Pharmacoepidemiol Drug Saf. 2011;20(10):1057-63.
  31. Wallerstedt SM, Gleerup H, Sundstrom A, Stigendal L, Ny L. Risk of clinically relevant bleeding in warfarin-treated patients–influence of SSRI treatment. Pharmacoepidemiol Drug Saf. 2009;18(5):412-6.
  32. Walan A, Bader J-P, Classen M, Lamers CBHW, Piper DW, Rutgersson K, et al. Effect of Omeprazole and Ranitidine on Ulcer Healing and Relapse Rates in Patients with Benign Gastric Ulcer. New England Journal of Medicine. 1989;320(2):69-75.
  33. Oddsson E, Gudjonsson H, Thjodleifsson B. Comparison between ranitidine and omeprazole for protection against gastroduodenal damage caused by naproxen. Scand J Gastroenterol. 1992;27(12):1045-8.
  34. Ray WA, Chung CP, Murray KT, Smalley WE, Daugherty JR, Dupont WD, et al. Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding. Jama. 2018;320(21):2221-30.
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  36. Graham DY, Agrawal NM, Roth SH. Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial. Lancet. 1988;2(8623):1277-80.
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Creation and Revision Dates
Created: 11/1/2019
Last revision: 11/1/2019
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