Adverse Interactions Between Warfarin and Nonsteroidal Antiinflammatory Drugs: Mechanisms,Clinical Significance,and Avoidance

Abstract

French

Objective:

To review the mechanisms and clinical significance of adverse interactions between warfarin and nonsteroidal antiinflammatory drugs (NSAIDs) and discuss how these interactions can be avoided.

Data Sources:

Previous studies of interactions between warfarin and NSAIDs or reports of adverse interactions were identified from a MEDLINE search (1976 to present) and from the reference lists of pertinent articles.

Study Selection And Data Extraction:

All articles were considered for inclusion in the review. Pertinent information was selected for discussion.

Data Synthesis:

All NSAIDs can prolong bleeding time by inhibiting platelet function. High-dose aspirin has a direct hypoprothrombinemic effect. Phenylbutazone and its analogs enhance the hypoprothrombinemic effect of warfarin through a pharmacokinetic interaction by inhibiting the hepatic metabolism of warfarin. Mefenamic acid also enhances the anticoagulant effect of warfarin, but the mechanism is not known. The clinical relevance of protein binding displacement in the interaction between warfarin and NSAIDs has been overstated, although a significant one may be more likely in the presence of high concentrations of NSAIDs in patients with slow elimination of warfarin (e.g., those with severe heart failure or impaired liver function). NSAIDs can induce gastrointestinal bleeding, which is likely to be more severe if warfarin is also given.

Conclusions:

The combined use of warfarin and NSAIDs is generally discouraged because of the increased risk of bleeding in these patients. In patients receiving warfarin who also require NSAIDs, phenylbutazone and its analogs, high-dose aspirin, mefenamic acid, excessive use of topical methyl salicylate, and NSAIDs that are associated with a higher risk of bleeding peptic ulcers should be avoided. Patients should be closely monitored for anticoagulant control and bleeding complications during the combined use of warfarin and NSAIDs.

Get full access to this article

View all access options for this article.

References

Serlin

, Breckenridge

. Drug interactions with warfarin. Drugs 1983; 25: 610–20.

O'Reilly

. Warfarin metabolism and drug–drug interactions. Adv Exp Med Biol 1987; 214: 205–12.

Buckley

, Dawson

. Drug interactions with warfarin. Med J Aust 1992; 57: 479–83.

Freedman

, Olatidoye

. Clinically significant drug interactions with the oral anticoagulants. Drug Saf 1994; 10: 381–94.

O'Callaghan

, Thompson

, Russell

. Combining NSAIDs with anticoagulants: yes and no. Can Med Assoc J 1984; 131: 857–9.

Eble

, West

, Link

. A comparison of the isomers of warfarin. Biochem Pharmacol 1966; 15: 1003–6.

Hewick

, McEwan

Plasma half-lives, plasma metabolites and anticoagulant efficacies of the enantiomers of warfarin in man. J Pharm Pharmacol 1973; 25: 458–65.

Holford

NHG

. Clinical pharmacokinetics and pharmacodynamics of warfarin. Understanding the dose–effect relationship. Clin Pharmacokinet 1986; 11: 483–504.

Saour

, Gallus

Warfarin: is it time to reduce target ranges again?

Aust N Z J Med 1993; 23: 692–6.

10.

Landefeld

, Goldman

Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med 1989; 87: 144–52.

11.

Landefeld

, Beyth

. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993; 95: 315–28.

12.

Routledge

. Clinical pharmacology and the art of bespoke prescribing. Br J Clin Pharmacol 1988; 26: 339–45.

13.

Routledge

, Chapman

, Davies

, Rawlins

. Factors affecting warfarin requirements. A prospective population study. Eur J Clin Pharmacol 1979; 15: 319–22.

14.

Bjornsson

. Anticoagulants. In: Williams

, Brater

, Mordenti

eds. Rational therapeutics. A clinical pharmacologic guide for the health professional. New York: Marcel Dekker, 1990: 541–77.

15.

Chan

TYK

, Tsoi

, Critchley

JAJH.

The determinants of warfarin requirements in Chinese patients. Pharmacoepidemiol Drug Saf 1992; 1: 281–2.

16.

Pullar

, Capell

. Interaction between oral anti-coagulant drugs and non-steroidal anti-inflammatory agents: a review. Scott Med J 1983; 28: 42–7.

17.

Tonkin

, Wing

LMH

. Interactions of non-steroidal anti-inflammatory drugs. Baillieres Clin Rheumatol 1988; 2: 455–83.

18.

Johnson

, Seideman

, Day

. Adverse drug interactions with nonsteroidal anti-inflammatory drugs (NSAIDs): recognition, management and avoidance. Drug Saf 1993; 8: 99–127.

19.

Johnson

, Seidemann

, Day

. NSAID-related adverse drug interactions with clinical relevance. An update. Int J Clin Pharmacol Ther 1994; 32: 509–32.

20.

Quick

, Clesceri

Influence of acetylsalicylic acid and salicylamide on the coagulation of blood. J Pharmacol Exp Ther 1960; 128: 95–8.

21.

Rothschild

. Hematologic perturbations associated with salicylate. Clin Pharmacol Ther 1979; 26: 145–52.

22.

Diana

, Veronich

, Kapoor

. Binding of non-steroidal anti-inflammatory agents and their effect on binding of racemic warfarin and its enantiomers to human serum albumin. J Pharm Sci 1989; 78: 195–9.

23.

Mackichan

. Protein binding drug displacement interactions—fact or fiction? Clin Pharmacokinet 1989; 16: 65–73.

24.

Banfield

, O'Reilly

, Chan

, Rowland

Phenylbutazone–warfarin interaction in man: further stereochemical and metabolic considerations. Br J Clin Pharmacol 1983; 16: 669–75.

25.

Roth

, Majerus

. The mechanism of the effects of aspirin on human platelets. I. Acetylation of a particular fraction protein. J Clin Invest 1975; 56: 624–32.

26.

McQueen

, Facoory

, Faed

. Non-steroidal anti-inflammatory drugs and platelet function. N Z Med J 1986; 99: 358–60.

27.

Shorr

, Ray

, Daugherty

, Griffin

. 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: 1665–70.

28.

Hurlen

, Erikssen

, Smith

, Arnesen

, Rollag

Comparison of bleeding complications of warfarin and warfarin plus acetylsalicylic acid: a study in 3166 out-patients. J Intern Med 1994; 236: 299–304.

29.

Hawkey

. Non-steroidal anti-inflammatory drugs and peptic ulcers: facts and figures multiply, but do they add up? BMJ 1990; 300: 278–84.

30.

Langman

MJS

, Brooks

, Hawkey

, Silverstein

, Yeomans

Nonsteroidal anti-inflammatory drug associated ulcer: epidemiology, causation and treatment. J Gastroenterol Hepatol 1991; 6: 442–9.

31.

Langman

MJS

, Weil

, Wainwright

, Lawson

, Rawlins

, Logan

RFA

Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994; 343: 1075–8.

32.

Fries

, Williams

, Bloch

, Michel

. Nonsteroidal anti-inflammatory drug-associated gastropathy: incidence and risk factor models. Am J Med 1991; 91: 213–22.

33.

Holmes

. Pharmacology of the fenamates: IV. Toleration by normal human subjects. Ann Phys Med 1966; 8(suppl):36–49.

34.

O'Reilly

, Sahud

, Aggeler

. Impact of aspirin and chlorthalidone on the pharmacodynamics of oral anticoagulant drugs in man. Ann N Y Acad Sci 1971; 179: 173–86.

35.

Serlin

, Mossman

, Sibeon

, Tempero

, Breckenridge

. Interaction between diflunisal and warfarin. Clin Pharmacol Ther 1980; 28: 493–8.

36.

Ermer

, Hicks

, Wheeler

, Kraml

, Jusko

. Concomitant etodolac affects neither the unbound clearance nor the pharmacologic effect of warfarin. Clin Pharmacol Ther 1994; 55: 305–16.

37.

Savitsky

, Terzakis

, Bina

, Chiccarelli

, Haynes

Fenbufen–warfarin interaction in healthy volunteers (abstract). Clin Pharmacol Ther 1980; 27: 284.

38.

Goncalves

Influence of ibuprofen on haemostasis in patients on anticoagulant therapy. J Int Med Res 1973; 1: 180–3.

39.

Penner

, Abbrecht

. Lack of interaction between ibuprofen and warfarin. Curr Ther Res 1975; 18: 862–71.

40.

Schulman

, Henriksson

Interaction of ibuprofen and warfarin on primary haemostasis. Br J Rheumatol 1989; 28: 46–9.

41.

Vesell

, Passananti

, Johnson

. Failure of indomethacin and warfarin to interact in normal human volunteers. J Clin Pharmacol 1975; 15: 486–95.

42.

Mieszczak

, Winther

Lack of interaction of ketoprofen with warfarin. Eur J Clin Pharmacol 1993; 44: 205–6.

43.

Toon

, Holt

, Mullins

FGP

, Bullingham

, Aarons

, Rowland

Investigations into the potential effects of multiple dose ketorolac on the pharmacokinetics and pharmacodynamics of racemic warfarin. Br J Clin Pharmacol 1990; 30: 743–50.

44.

Ravic

, Johnson

, Turner

, Ferber

. A study of the interaction between lornoxicam and warfarin in healthy volunteers. Hum Exp Toxicol 1990; 9: 413–4.

45.

Fitzgerald

. Double-blind study to establish whether there is any interaction between nabumetone and warfarin in healthy male volunteers. In: Panayi

, Price

, Rotman

eds. Nabumetone, a novel anti-inflammatory. Vol 69. London: Royal Society of Medicine, 1985: 47–52.

46.

Hilleman

, Mohiuddin

, Lucas

Jr. Nonsteroidal antiinflammatory drug use in patients receiving warfarin: emphasis on nabumetone. Am J Med 1993; 95(suppl 2A):S30–4.

47.

Slattery

, Levy

, Jain

, McMahon

. Effect of naproxen on the kinetics of elimination and anticoagulant activity of a single dose of warfarin. Clin Pharmacol Ther 1979; 25: 51–60.

48.

Jain

, McMahon

, Slattery

, Levy

Effect of naproxen on the steady-state serum concentration and anticoagulant activity of warfarin. Clin Pharmacol Ther 1979; 25: 61–6.

49.

Auteri

, Bruni

, Blardi

, Di Renzo

, Pasqui

, Saletti

Clinical study on pharmacological interaction between nimesulide and warfarin. Int J Clin Pharmacol Res 1991; 11: 267–70.

50.

Loftin

, Vesell

. Interaction between sulindac and warfarin: different results in normal subjects and in an unusual patient with a potassium-losing renal tubular defect. J Clin Pharmacol 1979; 19: 733–42.

51.

Eichler

, Jung

, Kyrie

, Rotter

, Korn

Absence of interaction between tenoxicam and warfarin. Eur J Clin Pharmacol 1992; 42: 227–9.

52.

Koch-Weser

, Sellers

. Drug interactions with coumarin anticoagulants. N Engl J Med 1971; 285: 547–58.

53.

Fox

. Potentiating of anticoagulants caused by pyrazole compounds. JAMA 1964; 188: 320–1.

54.

Eisen

. Combined effect of sodium warfarin and phenylbutazone. JAMA 1964; 189;64–5.

55.

Aggeler

, O'Reilly

, Leong

, Kowitz

. Potentiation of anticoagulant effect of warfarin by phenylbutazone. N Engl J Med 1967; 276: 496–501.

56.

Bull

, MacKinnon

Phenylbutazone and anticoagulant control. Practitioner 1975; 215: 767–9.

57.

Hobbs

, Miller

, Thornley

. Potentiation of anticoagulant therapy by oxyphenylbutazone: a probable case. Postgrad Med J 1965; 41: 563–5.

58.

Powell-Jackson

. Interaction between azapropazone and warfarin. Br Med J 1977; 1: 1193–4.

59.

Green

, Hort

, Korn

HET

, Leach

Potentiation of warfarin by azapropazone (letter). Br Med J 1977; 1: 1532.

60.

Win

, Mitchell

, Jones

PAE

, French

. Azapropazone and warfarin. BMJ 1991; 302: 969–70.

61.

Thompson

, Serjeant

Potentially serious interaction of warfarin with sulfinpyrazone (letter). Med J Aust 1981; 1: 41.

62.

O'Reilly

. Stereoselective interaction of sulfinpyrazone with racemic warfarin and its separated enantiomorphs in mart. Circulation 1982; 65: 202–7.

63.

Beeley

Azapropazone and warfarin (letter). BMJ 1991; 302: 1341.

64.

Justice

, Kline

. Analgesics and warfarin. A case that brings up questions and cautions. Postgrad Med 1988; 83:217–8,220.

65.

Koch-Weser

Hemorrhagic reactions and drug interactions in 500 warfarin-treated patients (abstract). Clin Pharmacol Ther 1973; 14: 139.

66.

Chan

TYK

, Lui

, Chung

, Luk

, Critchley

JAJH.

Adverse interaction between warfarin and indomethacin. Drug Saf 1994; 10: 267–9.

67.

Flessner

, Knight

Prolongation of prothrombin time and severe gastrointestinal bleeding associated with combined use of warfarin and ketoprofen (letter). JAMA 1988; 259: 353.

68.

Ross

JRY

, Beeley

Sulindac, prothrombin time, and anticoagulants (letter). Lancet 1979; 2: 1075.

69.

Thatcher

, George

Retropharyngeal hematoma as a new cause of acute upper airway obstruction in rheumatoid arthritis. J Rheumatol 1987; 14: 1172–3.

70.

Koren

, Cochran

, Janes

. Tolmetin–warfarin interaction (letter). Am J Med 1987; 82: 1278–9.

71.

Yip

ASB

, Chow

, Tai

, Cheung

. Adverse effect of topical methylsalicylate ointment on warfarin anticoagulation: an unrecognized potential hazard. Postgrad Med J 1990; 66: 367–9.

72.

Littleton

Jr.

Warfarin and topical salicylates (letter). JAMA 1990; 263: 2888.

73.

Tam

, Chan

TYK

, Leung

, Critchley

JAJH.

Warfarin interactions with Chinese traditional medicines: danshen and methyl salicylate medicated oil. Aust N Z J Med 1995; 25: 258.

74.

ACT

, Chan

, Yeung

JHK

, Woo

. The effects of danshen (Salvia miltiorrhiza) on pharmacokinetics and pharmacodynamics of warfarin in rats. Eur J Drug Metab Pharmacokinet 1992; 17: 257–62.

75.

Turpie

, Gent

, Laupacis

, Latour

, Gunstensen

, Basile

A comparison of aspirin and placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med 1993; 329: 524–9.

76.

Self

, Evans

, Ferguson

Drug enhancement of warfarin activity (letter). Lancet 1975; 2: 557–8.

77.

Rhodes

, Rhodes

, Klein

, Sintek

. A warfarin–piroxicam interaction. Drug Intell Clin Pharm 1985; 19: 556–8.

78.

Mallet

, Cooper

. Prolongation of prothrombin time with the use of piroxicam and warfarin. Can J Hosp Pharm 1991; 44: 93–4.

79.

Carter

. Potential effect of sulindac on response of prothrombin-time to oral anticoagulants (letter). Lancet 1979; 2: 698–9.

80.

Rodriguez

LAG

, Jick

Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994; 343: 769–72.

81.

Redwood

, Taylor

, Bain

, Matthews

. The association of age with dosage requirement for warfarin. Age Ageing 1991; 20: 217–20.

82.

James

, Britt

, Raskino

, Thompson

. Factors affecting the maintenance dose of warfarin. J Clin Pathol 1992; 45: 704–6.

83.

Routledge

, Chapman

, Davies

, Rawlins

. Pharmacokinetics and pharmacodynamics of warfarin at steady state. Br J Clin Pharmacol 1979; 8: 243–7.

84.

Shepherd

AMM

, Hewick

, Moreland

, Stevenson

. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol 1977; 4: 315–20.

85.

Hylek

, Singer

. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120: 897–902.

86.

Chan

TYK

. Recognizing increased sensitivity to warfarin in liver dysfunction secondary to congestive heart failure. Pharmacoepidemiol Drug Saf 1995 (in press).

87.

Williams

, Schary

, Blaschke

, Meffin

, Melmon

, Rowland

Influence of acute viral hepatitis on disposition and pharmacologic effect of warfarin. Clin Pharmacol Ther 1976; 20: 90–7.

88.

Chan

TYK

, Critchley

JAJH

, Chan

JCN

, Tomlinson

, Chan

MTV

. Disease profiles in Chinese in Hong Kong: an analysis of the primary diagnoses in 561 acute hospital medical admissions. Southeast Asian J Trop Med Public Health 1993; 24: 766–8.

89.

Chan

TYK

, Chan

JCN

, Tomlinson

, Critchley

JAJH.

Adverse reactions to drugs as a cause of admissions to a general teaching hospital in Hong Kong. Drug Saf 1992; 7: 235–40.