Contextual drug interaction decision support algorithm for warfarin - Nonsteroidal anti-inflammatory drugs (NSAIDs)


Concurrent use of both warfarin - Nonsteroidal anti-inflammatory drugs (NSAIDs) puts patients at a significant risk of bleeding that warrants appropriate management strategies. This decision support algorithm is designed to help provide appropriate alerts at the time of prescribing. 


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)

Creation Date

Artifact Creation and Usage


Richard Boyce (rdb20@pitt.edu), Daniel Malone, Philip Hansten, John Horn, Andrew Romero, Sheila Gephart, Eric Chou. 

IP Attestation The author asserts that this artifact has been developed in compliance with the intellectual property rights attributed to the source material.

This potential drug-drug interaction knowledge artifact is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License (CC BY-NC-SA 3.0). For more details on this license: https://creativecommons.org/licenses/by-nc-sa/3.0/

MeSH Topics
Implementation Details
Engineering Details

Data from a urban tertiary care facility was used to identify high-priority DDIs for contextualized alerting. A panel of DDI experts developed algorithms to incorporate drug and patient characteristics that affect the relevance of such warnings. The algorithms were then applied to both synthetic and real-world EHR data. See the Implementation Guide document for further details.

Repository Information
Knowledge Level

Structured code that is interpretable by a computer (includes data elements, value sets, logic)

Purpose and Usage
Supporting Evidence
  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. PMID: 16804099
  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. PMID:16174833
  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. PMID:16458764
  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. PMID:21671894
  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. PMID: 16086703
  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. PMID: 24267289
  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. PMID: 21373261
  8. Goldstein JL, Cryer B. Gastrointestinal injury associated with NSAID use: a case study and review of risk factors and preventative strategies. Drug Healthc Patient Saf. 2015;7:31-41. PMID: 25653559
  9. Pilotto A, Seripa D, Franceschi M, Scarcelli C, Colaizzo D, Grandone E, et al. Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P450 2C9 polymorphisms. Gastroenterology. 2007;133(2):465-71. PMID: 17681167
  10. Fawzy AM, Lip GYH. Pharmacokinetics and pharmacodynamics of oral anticoagulants used in atrial fibrillation. Expert Opin Drug Metab Toxicol. 2019;15(5):381-98. PMID: 30951640
  11. Ghosh R, Alajbegovic A, Gomes AV. NSAIDs and Cardiovascular Diseases: Role of Reactive Oxygen Species. Oxid Med Cell Longev. 2015;2015:536962. PMID: 26457127
  12. Meek IL, Van de Laar MA, H EV. Non-Steroidal Anti-Inflammatory Drugs: An Overview of Cardiovascular Risks. Pharmaceuticals (Basel). 2010;3(7):2146-62. PMID: 27713346
  13. Rucker D, Dhamoon AS. Physiology, Thromboxane A2. StatPearls. Treasure Island (FL): StatPearls Publishing
    StatPearls Publishing LLC.; 2019. PMID: 30969639
  14. Suleyman H, Demircan B, Karagoz Y. Anti-inflammatory and side effects of cyclooxygenase inhibitors. Pharmacol Rep. 2007;59(3):247-58. PMID: 17652824
  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. PMID: 10868317
  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. PMID: 16164494
  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. PMID: 19809010
  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. PMID: 15668365
  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. PMID: 15138157
  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. PMID: 14970301
  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. PMID: 20191029
  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. PMID: 2271233
  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. PMID: 28520347
  24. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal Toxicity of Nonsteroidal Antiinflammatory Drugs. New England Journal of Medicine. 1999;340(24):1888-99. PMID: 10369853
  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. PMID: 8333804
  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. PMID: 11522004
  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. PMID: 21731754
  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. PMID: 24285759
  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. PMID: 17269842
  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. PMID: 22039594
  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. PMID: 19301238
  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. PMID: 2643037
  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. PMID: 1475621
  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. PMID: 30512099
  35. Ray WA, Chung CP, Murray KT, Smalley WE, Daugherty JR, Dupont WD, et al. Association of Proton Pump Inhibitors With Reduced Risk of Warfarin-Related Serious Upper Gastrointestinal Bleeding. Gastroenterology. 2016;151(6):1105-12.e10. PMID: 27639805
  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. PMID: 2904006
  37. 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. PMID: 28520347
  38. Masclee GM, Valkhoff VE, Coloma PM, de Ridder M, Romio S, Schuemie MJ, et al. Risk of upper gastrointestinal bleeding from different drug combinations. Gastroenterology. 2014;147(4):784-92.e9; quiz e13-4. PMID: 24937265
Artifact Representation

Concomitant exposure to warfarin and an NSAID

Interventions and Actions

The algorithm first identifies basic concomitant exposures of warfarin and NSAIDs. Among these concomitant exposures, if the patient is on a proton pump inhibitor (PPI) or misoprostol during a concomitant exposure, a Class 2/3 (Yellow) alert is fired. If not, the algorithm then identifies whether or not a patient is able to start on an appropriate PPI. Patients unable to do so yield a Class 1 (Red) alert, while if a patient is able to do so, a Class 2/3 (Yellow) alert is fired.

  • Class 4: Green: No Special Precautions
  • Class 2/3: Yellow: Usually Avoid Combination or Minimize Risk
    •  For Warfarin – NSAIDS rule:
      • Recommendation: Assess risk and take action if necessary
      • Rationale: Possible increased risk of bleeding
  • Class 1: Red: Avoid Combination
    • For Warfarin – NSAIDS rule:
      • Recommendation: Use only if benefit outweighs risk
      • Rationale: Increased bleeding risk likely
Testing Experience
Pilot Experience

The algorithm has been validated using synthetic data but it has not yet been piloted in a clinical setting.