DrugInteractions
ADVERSE INTERACTIONS BETWEEN WARFARIN AND
NONSTEROIDAL ANTIINFLAMMATORY DRUGS: MECHANISMS,
CLINICAL SIGNIFICANCE, AND AVOIDANCE
Thomas YK Chan
OBJEL'TIVE: To review the mechanisms and clinical significance of
adverse interactions between warfarin and nonsteroidal anti-
inflammatory drugs(NSAIDs) and discuss how theseinteractions
can be avoided.
DATA SOURCFS: Previous studies of interactions between warfarin
and NSAlDsor reports of adverse interactions wereidentified from
a MEDLINE search(1976to present) and fromthe reference listsof
pertinent articles.
STIJDY SELECTION ANDDATA EXTRACTION: All articles wereconsidered
for inclusion in the review. Pertinent information was selected for
discussion.
DATA SYNTIIESIS: 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 effectof warfarin through a
pharmacokinetic interaction by inhibiting the hepatic metabolism of
warfarin. Mefenamic acidalsoenhances the anticoagulant effectof
warfarin, but the mechanism is not known. The clinical relevance of
protein binding displacement in the interaction between warfarin
and NSAlDshas beenoverstated. although a significant one may be
morelikelyin the presence of highconcentrations of NSAIDs in
patients withslowelimination of warfarin (e.g.,thosewithsevere
heartfailure or impaired liverfunction). NSAlDscan induce
gastrointestinal bleeding, which is likely to be moresevereif
warfarin is alsogiven.
CONCLUSIONS: The combined use of warfarin and NSAIDs is
generally discouraged because of the increased risk of bleeding in
thesepatients. In patients receiving warfarin who also require
NSAIDs, phenylbutazone and its analogs, high-dose aspirin.
mefenamic acid,excessive use of topical methyl salicylate. and
NSAlDsthat are associated witha higherriskof bleeding peptic
ulcers shouldbe avoided. Patients shouldbe closely monitored for
anticoagulant control and bleeding complications duringthe
combined use of warfarin and NSAlDs.
Ann Pharmacother 1995;29:1274-83.
Thomas YK Chan MBChB FRCP (Edin), Associate Professor and Physician, De-
partment of Clinical Pharmacology, The Chinese University of Hong Kong,
Prince of Wales Hospital, Shatin, New Territories, Hong Kong, FAX 852/
26373929
Reprints: Thomas YK Chan MBChR FRCP (F..din)
1274 • TheAnnalsofPharmacotherapy • /995 December. Volume 29
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WARFARIN IS COMMONLY USED in the treatment of thrombo-
embolic disease. Optimal therapy with this drug must aim
for a fine balance between prevention of intravascular
thrombosis and the production of unwanted bleeding. Sev-
eral factors may affect an individual's response to warfarin,
including age, diet, disease states, and drug interactions.
Numerous drugs have been reported to interact with war-
farin.!" These adverse interactions may result in loss of an-
ticoagulant control and serious consequences. Extra care
should, therefore, be taken with the introduction of any
new drug after stabilization of the warfarin dosage.
Despite extensive clinical experience with both warfarin
and aspirin and other nonsteroidal antiinflammatory drugs
(NSAIDs), physicians are uncertain as to the safety of us-
ing them in combination! Although patients receiving war-
farin are routinely advised to avoid NSAIDs, the risk of
bleeding during combination therapy and whether certain
individuals are at particular risk have not been well de-
fined. In this article, previous reports of interactions be-
tween warfarin and NSAIDs and the possible mechanisms
for these interactions are reviewed and some practical guid-
ance on prescribing is given.
ClinicalPharmacology of Warfarin
Warfarin sodium is a racemic mixture of 2 optical iso-
mers, R- and S-warfarin. These enantiomers are metabo-
lized through different pathways and have different half-
lives and potency; S-warfarin is 5 times more potent,' but
is eliminated more rapidly than R-warfarin.7
Warfarin is essentially completely absorbed after oral
administration, with the peak concentration occurring 2-6
hours after ingestion." Warfarin has a relatively small vol-
ume of distribution of approximately 10 U70 kg. The high
degree of binding of racemic warfarin to plasma albumin,
more than 99% at therapeutic concentrations, can explain
its clinical pharmacology: the prolonged half-life and bio-
logic effect.' At any given time, only the unbound portion
is active and available to be metabolized by the liver. The
average biologic half-life in humans is about 35 hours,
which means that it takes about a week to reach steady-
state,"
 Warfarin reversibly binds and inhibits vitamin K epox-
ide reductase and vitamin K quinonereductase.'These en-
zymes are responsible for converting the biologically inac-
tive vitamin K epoxide to active vitamin K hydroquinone.
Thus, warfarin inhibits the final activation step in the syn-
thesis of vitamin K-dependent clotting factors (factors II,
VII, IX, and X and protein C and protein S). As warfarin
competes with vitamin K for receptors, vitamin K content
in the diet can be an importantdeterminant of anticoagula-
tion.
The anticoagulant effect is measured with the interna-
tional normalized ratio (INR), which is a standardized pro-
thrombin time (PI'). Different therapeutic rangesfor differ-
ent clinical indications have been used." The target range
for the INR is critical becausethe level of anticoagulant ef-
fect is the major determinant of bleeding. The riskof bleed-
ing is increased in the elderly" and is highestat the start of
therapy." The risk for major bleeding during the first
month of therapy is approximately 10 times the risk after
the first year of therapy. The aim of treatment is to achieve
the minimum anticoagulant effect required to prevent
thrombosis or embolism.
Patients vary widely in the dosage of warfarin required
to maintainthe INR at any given level." Variation of up to
20-fold has been described in some cases,although 90% of
white patients require a daily dosage of 2-10 mg to main-
tain an INR of 1.8-2.5.J3Variation appears to be approxi-
matelyequally the result of differences in the pharmacoki-
netics (abouta 6-fold variation in totalclearance) and phar-
macodynamics (about a 6.5-fold variation in plasma free
concentration-effectrelationship) of the drug." The mean
maintenance daily dosageis considerably less in Chinese(3
mg) than in white patients (4-6 mg)." In both ethnic
groups, the age of the patientrather than body weightis an
importantdeterminant of warfarin requirement.P"
Interactions Between Warfarin and NSAIDs:Possible
Mechanisms
There are several mechanisms by which NSAIDs may
increase the likelihoodand severityof bleeding in patients
receiving warfarin. I -5,16-19
DIRECf HYPOPROTIlROMBINEMlC EFFECT OF ASPIRIN
Aspirin and other salicylates may have a hypoprothrom-
binemic effect by depressing the vitamin K-dependent
synthesis of clottingfactors Vll, IX, and X. However, such
an action only becomes significant if the equivalent of
more than 6 g (for a 70-kg man) of aspirin per day has
been ingested." The PT is rarely prolonged unless the
serum salicylate concentrations are more than 300
mg/ml.," concentrations at which salicylate toxicity also is
more likely.
PHARMACOKINETIC MECHANISMS
Two major types of pharmacokinetic interactions have
been described: displacementof warfarin from plasma al-
bumin and inhibition of the metabolism of warfarin by
NSAIDs,l9 The role of protein bindingdisplacementin in-
teractions with warfarinhas been overstated},18,19 Although
most NSAIDs, which are also highly protein-bound, have
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been found to displace warfarin from plasma albumin
bindingsites in vitro,22 this interaction has only been dem-
onstratedin vivo with some NSAIDs.19 Moreover, in vivo
studies have shown that this displacementdoes not neces-
sarily increase the anticoagulant action of warfarin. An in-
crease in the plasmaconcentration of unbound (pharmaco-
logically active) warfarinfollowing the introduction of the
displacing NSAlD will be transient because of the con-
comitantincreasein the clearance of unboundwarfarin un-
til the previous concentration is reached." Thus, displace-
ment may be important only for intermittent warfarin use
and on introduction and withdrawal of the displacing
NSAIDs.3 In such situations, the effect again is transient
and steady-state shouldbe reachedafter 7-10 days. A clin-
ically significant interaction also may be more likelyin the
presence of high concentrations of NSAIDs in patients
with slow elimination of warfarin (e.g., those with severe
heart failure or impairedliver function)."
Phenylbutazone substantially inhibits the metabolism of
S-warfarin while increasing the hepatic clearance of R-
warfarin." The net result is increased anticoagulation with-
out a change in the overall clearance of racemic warfarin.
It is likely that analogs of phenylbutazone (oxyphenbuta-
zone, apazone,and sulfinpyrazone) will interactwith war-
farin in the same manner. Similar data for other NSAlDs
are not available, as plasma concentrations of total war-
farin rather than its isomers have been measuredin studies
of interaction with warfarin (Table 1).
PHARMACODYNAMIC MECHANISMS
Twopharmacodynamic interactions havebeendescribed:
dir~ct effects on platelets and inductionof upper gastroin-
testinal (01) bleeding'? Aspirin irreversibly acetylates plate-
let cyclooxygenase at low or high doses and produces irre-
versible effects on platelet function that persist for the life
of the aspirin-treated platelet." Platelet aggregation thus
may be inhibitedand the bleeding time prolonged. Similar,
but usually lesser, effectson plateletfunction may be seen
with nonaspirin NSAIDs, but unlike aspirin, these effects
are lost when the drug or any active metabolites are re-
moved from the circulation.' Thus, the effects are usually
reversible in 24 hours for short-acting NSAlDs, but may
continue for many days with longer-acting NSAIDS.Ui Be-
cause of the adverse effects on hemostasis, NSAlDs in-
crease the risk of bleeding from the GI tract" or other
sites:l8 during concomitant use.
Several studies have shown that a person exposed to
NSAIDs has 3-4 times the risk of upper 01 bleeding, per-
foration, or both than a personwho has not been exposed."
A wide range of mechanisms could explainthe occurrence
of NSAlD-induced gastroduodenal mucosal damage, in-
cluding the inhibition of bicarbonate secretion, effects on
mucus formation, and vascular actions." The individual
risks are low, of the order of 1 episode for every 10000
NSAID prescriptions issued to people aged 60 years and
older in the UK,31 Becausemany such prescriptions are is-
sued, there are many episodes. In a study of patients with
rheumatoid arthritis, the incidence of hospitalization be-
cause of upper 01 bleedingin patientstaking NSAIDs was
1.58% per year compared with 0,3% in those not taking
the agents." In additionto old age, other clinical variables
of predictive value included use of prednisone, disability,
 Table I. Studies of Interactions Between Warfarin and Nonsteroidal Antiinflammatory Drugs
NSAID REF. SUBJECTS STUDY DESIGN MAJOR FINDINGS

Aspirin Holmes 12 healthy men all given warfarin (plasma prothrombin further decreases in plasma prothrombin concentrations
(1966)33 concentrations 1Q-.-20% of normal), after aspirin (2.75%) or mefenamic acid (3.49%);
then placebo, mefenamic acid 500 mg microscopic hematuria in 3 subjects
qid, placebo, aspirin 650 mg qid, or,
mefenamic acid, placebo, aspirin, pla-
cebo, each given for I wk
O'Reilly et al. 13 healthy men, 13 men taking stabilized dose of warfarin a decrease in prothrombin activity in 3 men taking low-
(1971)34 aged 21-28 y for ~2 wk given aspirin 0.65 g tid for 7 d dose aspirin and all 4 men taking high-dose aspirin;
=
(n 9) or 0.975 g tid for '5.7 d (n 4) =
bleeding in 2 men taking low-dose aspirin and in all 4
men taking high-dose aspirin
6 men taking warfarin (prothrombin bleeding time did not change with warfarin alone, but
activity <35% of normal for 7 d) given was prolonged from 4.0 to 10.3 min after aspirin added
aspirin 0.65 g tid for 3 d
Diflunisal Serlin et al. 5 healthy men, weeks 1-2,5 men receiving subthera- prothrombin complex activity fell (74% to 43%) in
(1980)35 aged 20--40 y peutic doses of warfarin (PT prolonged weeks 1-2, did not change in weeks 3-4, increased to
for a few seconds); weeks 3-4, warfarin >70% in weeks 5-6; plasma total warfarin concentra-
plus diflunisal 500 mg bid; weeks 5--6, tion fell by 39% and plasma free warfarin concentration
warfarin alone increased (1.02% to 1.34%) in weeks 3-4; plasma free
warfarin concentration returned to basal levels within a
few days of stopping diflunisal and plasma total warfarin
concentration returned to basal levels after 2 wk; difluni-
sal alone did not affect clotting factor activity
Etodolac Ermeret al. 18 healthy men, warfarin (20 mg on day I, 10 mg on during concomitant etodolac use, plasma total warfarin
(1994)36 aged 22-36 y days 2 and 3), etodolac 200 mg 12 concentration fell by 19%, total clearance increased by
hourly for 5 doses 13%, no change in peak PT response or area under the
curve of change in PT, when compared with warfarin
alone; most but not all subjects attained steady plasma
warfarin concentration by day 3, PT response varied
considerably among the group
Fenbufen Savitsky et al. 16 healthy days 1-10, warfarin 7.5 mg/d; days 11- 6 subjects withdrawn because PT >30 s; 5 subjects in
(1980)31 subjects 17, warfarin plus fenbufen 400 mg bid each group completed the study; days 11-17, fenbufen
= =
(n 8) or placebo (n 8); days 18-24, compared with placebo groups: PT (+1.9 s, NS), aPTT
=
fenbufen (n 8) or placebo (n 8) =
(+2 s, NS), warfarin concentration (-14%, p 0.03), =
similar warfarin disappearance rate and rate of normal-
ization of PT and aPTT
Ibuprofen Goncalves 50 patients factors II, VII, and X and aPTT assayed no significant changes in factors II, VII, and X concentra-
(1973)38 taking warfarin before and 7 d after ibuprofen 600- tions and aPTT before and after ibuprofen therapy
1200mg/d
Penner and 36 healthy men days 1-14, each group of 6 men given no changes in PT, aPTT, or plasma factors II, VII, IX,
Abbrecht aged 21--60 y placebo, ibuprofen 300 mg qid or 600 and X during or after 14 d of placebo or ibuprofen; sim-
(1975)39 mg qid, warfarin 7.5 rng/d, or warfarin ilar increases in PT and aPTT and similar decreases in
7.5 mg plus ibuprofen 300 mg qid or plasma factors II, VII, IX, and X during or after 14 d of
600 mgqid warfarin with or without ibuprofen; similar plasma war-
farin concentrations during or after 14 d of warfarin or
warfarin plus ibuprofen
Schulman and 19 patients aged patients receiving warfarin for 0.25-84 no change in PT after ibuprofen was added for I wk;
Henriksson 35-80 Ywith mo given ibuprofen 600 mg tid for I prolonged bleeding time on day 8 in 3 patients, 2 of
(1989)40 pulmonary wk whom also had microscopic hematuria or subcutaneous
thromboembol- hematomas; 3 of 16 patients with normal bleeding
ism and rheu- times developed subcutaneous hematomas
matic or non-
rheumatic
disorders
Indomethacin Vesell et al. 16 healthy men all subjects stabilized on warfarin thera- no differences between indomethacin and placebo with
(1975)41 aged 19-28 y py (PT 1.5-2.5 times control value) regard to changes in PT from baseline and the rate of
given indomethacin 100 mg/d or return to the pretreatment PT during recovery period
placebo for 5 d
19 healthy men all given warfarin 0.75 mglkg on days I no differences between indomethacin and placebo with
aged 22-27 y and 31; indomethacin 100 mgld or regard to effects on warfarin-induced hypoprothrom-
placebo on days 21 and 31 binemia or plasma warfarin half-life
Ketoprofen Mieszczak and 13 healthy men successive 7-d periods: run-in/keto- during ketoprofen use, no change in factors II, VII,liM
Winther aged 26-45 y profen!wash-outlplacebo or run-in! X, thrombin time and aPTT; massive lowering of plate-
(1993)° placebo/washoutlketoprofen; warfarin let aggregability (a 38-fold difference) by ADP
dosage adjusted during run-in period lasting for 24 h
(factors II, VII, and X lowered by 60%),
then fixed; ketoprofen 100 mg bid
given

= = =
ADP adenosine diphosphate; aPTT activated partial thromboplastin time; INR international normalized ratio; NS =not significant; NSAID =nonsteroidal
= =
antiinflammatory drug; OA osteoarthritis; PT prothrombin time; RA = rheumatoid arthritis.

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 Warfarin-NSAID Interactions

Table 1. Studies ofInteractions Between Warfarin and Nonsteroidal Antiinflammatory Drugs (continued)
NSAID REF. SUBJECTS STUDY DESIGN MAJOR FINDINGS

Ketorolac Toon et a\. 10 healthy men all received ketorolac 10 mg qid or ketorolac did not significantly affect the magnitude of
(1990)43 aged 20-32 y placebo for 12 d and warfarin 25 mg warfarin-induced changes in PT and clotting time, or the
on day 6; plasma warfarin enantiomers pharmacokinetics of warfarin enantiomers; ketorolac
measured at 0-168 h after administra- increased bleeding time by a factor of 1.35 compared
tion of warfarin; crossover after ;:::14 d with placebo
Lornoxicam Ravic eta\. 12 healthy men days 1-5, lornoxicam 4 mg/d; days 9-24, significant changes in PT (23.6 vs. 19.5 s), INR (1.48 vs.
(1990)44 aged 22-41 y lornoxicam plus warfarin to achieve an 1.23) and total serum warfarin concentration (1.02 vs.
INR of 1.4-1.6 for;:::6 consecutive 0.77 ug/rnl.) at the end of phase 2 compared with phase
days; days 25-33, warfarin alone at 3; the significant decreases in PT, INR, and serum total
same dosage warfarin concentrations from phase 2 to phase 3 sug-
gested a significant interaction
Mefenamic acid Holmes see aspirin
(1966)33
Nabumetone Fitzgerald" 12 healthy men all subjects stabilized on warfarin for 3 no significant differences between subjects treated with
wk (mean INR 2.6-3.8), then also given nabumetone or placebo with respect to INR, IT, or
nabumetone 2000 mg/d or placebo for bleeding time
2wk
Hilleman et a\. 58 patients tak- all patients receiving chronic warfarin no significant differences in INR before and after
(1993)46 ing warfarin therapy also given nabumetone 1000 nabumetone for 6 wk
with OA or RA or 2000 mg/d for 6 wk
Naproxen Slattery et al. 10 healthy men warfarin 50 mg on days I and 29; during concomitant use with naproxen, serum free war-
(1979)47 aged 24-31 y naproxen 375 mg bid on days 19-35 farin concentration increased by 13%, the total clear-
ance and intrinsic clearance of warfarin did not change,
the area above the prothrombin complex activity vs.
time curve did not change
Jain et a\. 10 healthy sub- days 1-25 warfarin in a dose to prolong in the 5 subjects who received a constant daily dose of
(1979)48 jects aged PT to 1.5-2.0 times the normal value; warfarin, no significant difference in the serum free or
25-65 y days 11-20, also received naproxen total warfarin concentrations and PT before, during, and
375 mg bid after naproxen; the others required frequent dose adjust-
ment prior to and during naproxen therapy and 2 had
hematuria (day 18) or bruise aftertrauma (day 12)
Nimesulide Auteri et al. 10 patients all received warfarin 5 mg/d and then no significant change in PT, aPTT, and bleeding time
(1991)49 nimesulide 100 mg bid for 7 d before and after nimesulide
Phenylbutazone Banfield et al. 3 healthy warfarin 1.5 mg/kg before and 4 d during concomitant use of phenylbutazone, elimination
(1983)24 subjects into a 12-d regimen of phenylbuta- half-life of S-warfarin increased (25 to 46 h) and R-war-
zone 100 mg tid farin decreased (37 to 25 h); peak unbound concentra-
tions of both enantiomers increased, unbound clearance
of S-warfarin decreased by 4-fold; unbound clearance
of R-warfarin was almost unchanged
Sulindac Loftin and 19 healthy men all subjects stabilized on warfarin no significant difference in PT or plasma warfarin con-
Vesell aged 21-31 y therapy (PT 1.5-2.5 times the control centrations between the 2 groups in the 2nd phase;
(1979)50 value), then received sulindac 200 mg after warfarin was stopped, PT and aPTT were higher
bid (n = 10) or placebo (n = 9) for 10 and returned more slowly to normal in the sulindac
d; warfarin was stopped after 7 group
d of coadministration
Tenoxicam Eichler et al. 16 healthy 8 subjects given warfarin 0.75 mg/kg on no significant difference in plasma warfarin-time profile
(1992)5\ subjects aged 2 occasions, 4 wk apart, with or without or PT between treatment cycles
19-35 y tenoxicam 20 mg/d in preceding 2 wk
8 subjects given tenoxicam 20 mg/d no effects on PT, aPTT, IT, activity of factors II, V, VII,
for 14 d IX, and X, and bleeding time
8 subjects stabilized on warfarin therapy no significant difference between treatment periods with
(INR 1.47-1.81) given tenoxicam 20 respect to INR and warfarin requirements
mg/d for 2 wk: tenoxicam then stopped
while warfarin continued for 4 more wk

= = =
ADP adenosine diphosphate; aPTT activated partial thromboplastin time; INR international normalized ratio; NS =not significant; NSAID =nonsteroidal
= = =
antiinflammatory drug; OA osteoarthritis; PT prothrombin time; RA rheumatoid arthritis; TT thrombin time. =

the doseof NSAIDs, and previous problems withNSAIDs.
Upper GI bleeding is expectedto be more pronounced in
patients takingwarfarin.
Determining the Risk ofAdverse Interactions Between
Warfarin and NSAIDs
Whetherall NSAIDs interactwith warfarin to a similar
extent and the safety in using these drugs in combination
can be determined at least in partby considering studies in
healthy subjects or patients and reports of adverse interac-
tionswith or without bleeding. Giventhat concurrent war-
farin therapy is expectedto increase the severity of bleed-
ing from peptic ulcers, the risk of pepticulceration associ-
ated with the use of individual NSAIDs also should be
considered. It is expected that adverse interactions between
these 2 drugs are more likelyto be of clinical significance
in subjects who are particularly sensitive to warfarin.

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Clinical Studies
The study design and major findings from the previous
studies of interactions between warfarin and aspirin,JJ.34
diflunisal," etodolac," fenbufen," ibuprofen,J8-40 indo-
methacin," ketoprofen," ketorolac," lornoxicam," mefe-
namic acid,JJ nabumetone.v-" naproxen.t'-" nimesulide,"
phenylbutazone." sulindacj" and tenoxicam" are shown in
Table l. 14,33-51
CAUTIONS
Aside from findings concerning phenylbutazone and its
analogs, findings fromstudies of interactions between war-
farin and other NSAIDs may not be extrapolated to all
clinical situations. First, individual differences with respect
to warfarin and NSAIDs do occur.! Second, patients re-
ceiving warfarin and NSAIDs in combination also may
have liverdysfunction, cardiac failure, or other serious ill-
nesses that require other medications.In many of these
studies, subjects weregiven warfarin in subtherapeutic dos-
es. INRs were seldom reported and therefore the intensity
of anticoagulation could not be judged. Apart from the
study concerning ketorolac or phenylbutazone, plasma
concentrations of racemic warfarin rather than its enan-
tiomers were measured. It is most important to remember
that, even in the absenceof pharmacokinetic interactions,
bleedingstill can occur because of pharmacodynamic in-
teractions.
BleedingComplications
There have been numerous reportsof bleeding compli-
cations in patients receiving long-term warfarin therapy
who also were taking NSAIDs. Minor or major bleeding
also was seen in healthy volunteers during the studies of
interactions between warfarin and aspirin.P-" mefenamic
acid," and naproxen" (Table I).
Phenylbutazone and its analogs potentiate the anticoag-
ulant effect of warfarin and increase the risk of hemor-
rhage in all patients.Z4.SZ-6Z It is expected thatall phenylbuta-
zone analogs also will substantially inhibitthe metabolism
of the more potent S-warfarin while enhancingthe elimi-
nation of R-warfarin.14•6z,6J
Because phenylbutazone and its analogs are now rarely
used in clinical therapeutics and potentiation of warfarin-
induced anticoagulant effect appears to be universal, previ-
ous reports of adverse interactions between these drugs
and warfarinare not considered further. Reports concern-
ing otherNSAIDs are summarized in Table 2.40,64-70
Bleedingcomplications following the.oral administra-
tion of ibuprofen,40,64 indomethacin,6S,66 ketoprofen," sulin-
dac,68,69 and tolmetin" have been reported. The first report
of an adverse interaction between indomethacin and war-
farincame from a prospective study of 500 warfarin-treat-
ed patients, but the clinical details were not included." In 1
reportconcerningibuprofen," a patient with normal liver
function took an unknown numberof 200-mg tabletsover
4 days and about 30 tabletsof Darvocet-N (propoxyphene
napsylate 100mg/acetaminophen 650 mg) over 3 days pri-
or to the onset of bleeding. Although the authors believed
that an adverse interaction between Darvocet-N and war-
farin was responsible for the change in PT and bleeding
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complications, ibuprofen could well have been the offend-
ing agent.
The hazard from the excessive use of topical analgesic
preparations containing methyl salicylate is not well recog-
nized. Three patients aged 41-65 years taking warfarin af-
ter placementof a prosthetic mitral valve had a markedly
prolonged INR (4.2-5.5), increasedblood salicylate con-
centrations(0.4-0.8 mmollL), and bleeding (bruisesin 2
and GI hemorrhage in I) after excessiveuse of such oint-
ments for myalgiaor osteoarthritis pain." An 85-year old
woman with congestive heart failure and atrial fibrillation
received warfarin for pulmonary embolism." She present-
ed with vaginal bleeding, ecchymosis over the left cheek,
the right flank, and the perineum, a decrease in hemoglo-
bin concentration from 117to 80 gIL, and a prolongation
of PT from 18.5 to 55.0 seconds. Duringthe week priorto
admission, she had applied large quantities of topical
methyl salicylate to the skin over her joints because of
arthralgias. She was given intravenous vitamin K and a
bloodtransfusion. Methyl salicylate in Chinese proprietary
medicines may interactwith warfarin in a similarmanner.
A 66-year-oldman receiving warfarin for rheumatic heart
disease and cerebral embolism had an INR of more than
5.5 and GI bleeding from undiagnosed gastric carcinoma
after he had applied Kwan Loong Medicated Oil (15%
methyl salicylate) to his entire chest wall becauseof chest
pain." He also took danshen (the root of Salvia miltior-
rhiza Bge), which has been shownto affect the elimination
of warfarin in rats."
Concomitant use of warfarin and low-doseaspirin is as-
sociated with an increased risk of bleeding. In 186patients
with mechanical heart valves or with tissue valves plus
atrial fibrillation or thromboembolism," adding aspirin
100 mg qd to warfarin treatment (targeted INR 3.0-4.5)
was associated with a 55% increase in bleeding and a 27%
increase in major bleeding episodes after an average fol-
low-up periodof 2.5 years compared with controls treated
with warfarinonly. However, the risk of the combination
therapy was more than offset by the major reduction in
systemic embolism or deaths from vascular causes.
The incidence of bleeding complications was compared
in 2026 patients treated with warfarin alone (targeted INR
2.5-4.2) and 1140patients treated with warfarin plus as-
pirin 150mg qd (targeted INR 2.2-2.8).18 The mainindica-
tionsfor warfarin therapy in the warfarin only and warfarin
plus aspirin groups were as follows: acute myocardial in-
farction (27.6% vs. 61.9%), unstable angina (5.7% vs.
21.0%), coronary artery bypass grafts (2.8% vs. 10.1 %),
prosthetic heart valve (9.5% vs. 2.0%),thromboembolism
(38.6% vs. 7.0%), and atrial fibrillation (7.8% vs. 1.6%).
After a total observation time of 4420 treatment-years, the
incidence of minor bleeding episodeswas significantly (p
< 0.(03) lower in the warfarin group than in the combined
therapy group (1.4% vs. 2.9%). However, the incidence of
serious(3.2% vs. 2.8%, not significant) or fatal (0.6% vs.
0.4%, not significant) bleeding episodesdid not differ be-
tween the 2 groups. In those with bleeding complications,
39% in the warfarin groupand 35% in the combined thera-
py grouphad an INR abovethe targeted range.
Concurrent use of warfarin and NSAIDs not containing
aspirin is associated with a higherincidence of hemorrhag-
ic peptic ulcers. In a retrospective cohort study of Ten-
nesseeMedicaid enrollees aged 65 yearsor older," the in-
 Warfarin-NSAID Interactions

Table2. Case Reportsof Bleeding Complications DuringCombinedUse of

Warfarin and Nonsteroidal Antiinflammatory Drugs"
DIAGNOSIS INDICATION
PATIENT (duration of (duration of CHANGES IN
NSAID REF. sex/age(y) warfarin therapy) NSAID therapy) PTRATIO COMPLICATIONS TREATMENT

Ibuprofen Schulman and 5 rheumatic PTE (0.3-48 mol rheumatic disorders subcutaneous hema-
Henriksson patients (600 mg tid for I wk) toma (n '" 4), mi-
(1989)40 croscopic hematuria
(see Table I) (n'" I)
Justice and M/24 loin pain, hematuria postconcussion pain PT 13.6 to skin bruising, oozing vitamin K
Kline syndrome (200 mg for> I d, also >100 s from shaving
(1988)64 took Darvocet-N) nicks
Indomethacin Koch-Weser clinical details not available
(1973)65
Chan et al. Ml57 DVT, hypertension, gout (~25 mg/d for INR <2.5 to 3.4 skin bruising, FFP
(1994)66 gout (6 d) ~lOd) hematuria
Ketoprofen Flessner and Ml62 dilated cardiomyopathy. pain (25 mg tid for 6 d) PT 18 t041 s bleeding duodenal transfusion,
Knight COPD, gout, carcin- and gastric ulcer, FFP
(1988)67 oma of posterior cri- esophagitis
coid region
Sulindac Ross and F/53 PTE, was taking flurbi- (100 mg bid for 3 INR 2.0 to 4.6 fresh blood per
Beeley profen 50 mg qid doses) rectum
(1979)68 (I mol
Thatcher and F/56 DVT. PTE (3 mol rheumatoid arthritis PT 17 to 26.6 s retropharyngeal vitamin K.
George hematoma FFP
(1987)69
Tolmetin Koren etal. Ml64 DVT, IODM. CRF, shoulder pain (400 mg PT 15-22 to epistaxis, occult vitamin K.
(1987)'0 IHD(4mo) bid for 3 doses) 70.2 s gastrointestinal FFP
bleeding

COPD '" chronic obstructive pulmonary disease; CRF '" chronic renal failure; DVT '" deep-vein thrombosis; FFP '" fresh frozen plasma; IODM '" insulin-de-
pendent diabetes mellitus; IHD '" ischemic heart disease; INR '" international normalized ratio; NSAID '" nonsteroidal antiinflammatory drug; PT", pro-
thrombin time; PTE", pulmonary thromboembolism.
"Refer to Table I for minor or major bleedings during studies of interactions between warfarin and aspirin,33.'"mefenamic acid," and naproxen" in healthy
subjects. and to text for reports involving topical methyl salicylate therapy.

cidenceof hospitalizations for hemorrhagic pepticulcersin
patients taking an anticoagulant was 10.2per 1000person-
years, more than 3 times that of those not taking an antico-
agulant. The incidenceof hospitalizations for hemorrhagic
peptic ulcers in patientstaking both warfarinand NSAIDs
not containing aspirin was 26.3 per 1000 person-years,
about 13 times that of those not taking either drug. The
prevalence of NSAIDuse among those takingan anticoag-
ulant was 13.5%, the same as in those who were not taking
anticoagulants.
LossofAnticoagulant Control Without Bleeding
Complications
An increase or a decrease in anticoagulanteffect when
an NSAID is given to or withdrawn from patients receiv-
ing warfarin therapy also suggests an adverse interaction
between the 2 drugs. There have been reports concerning
indomethacin," piroxicam,":" and sulindacso,67.79 given
orally(Table 3).
The INR of 8 patientsaged 15-64 years receiving war-
farin for prosthetic heart valves or mitral stenosis was
markedly increased from 1.9-2.6 to 3.3-5,2 after using
topicalmethyl salicylate ointmentfor osteoarthritis or my-
algia." They all had increasedblood salicylateconcentra-
tions (0.2-0.6 mmollL) on admission. A 68-year-old man
taking warfarin for atrialfibrillation experienced prolonga-
tion of INR from 1.3-1.5 to 2.5 after he had liberally ap-
plied topical trolarnine salicylate to his neck and shoulders
on severaloccasions becauseof pain."
Risk of Upper Gastrointestinal Bleeding with an NSAJD
In a population-based, retrospective, case-control study
of 1457 adults aged 25-77 years with upper GI bleeding
and perforation in the UK between 1990 and 1993,80 the
relative risk associated with current use of NSAIDs not
containing aspirin was 4.7. Previous upper GI bleeding
was the single most important predictorof the disease(rel-
ative risk 13.5). For all NSAIDs together, the risk was
greater for high doses than for low doses (relativerisk 7.0
vs. 2.6).Those taking apazone(23.4) and piroxicam (18.0)
had the highest riskof upperGI bleeding. All otherNSAIDs
with sufficient data for individual analysis (i.e., ibuprofen,
naproxen, diclofenac, ketoprofen, indomethacin) had rela-
tive risks similarto that for overallNSAID use.
In a prospective, case-controlstudy, 1144patients aged
60 years or older were admitted to hospitals in the UK
with bleeding peptic ulcers between 1987 and 199J.31 In
this study, peptic ulcer bleeding was strongly associated
with the use of NSAIDs other than aspirin during the 3
months before admission (relative risk 4.5). The relative
risk was lowest for ibuprofen (2.0) and diclofenac (4.2),
and intermediatefor indomethacin (11.3), naproxen (9.1),
and piroxicam (11.3). Apazone (31.5)and ketoprofen (23.7)
had the highest risks. Risks also increased with drug dose

The Annals ofPharmacotherapy • 1995 December, Volume 29 • 1279

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(low dose 2.5, intermediate dose 4.5, high dose 8.6) for all
NSAIDs combined.
Groups at Risk ofBleeding
Some individuals are expected to be particularly at risk
of more severe bleeding as a consequence of adverse inter-
actions between warfarin and NSAIDs. These include pa-
tientswho are more sensitive to warfarin" or proneto war-
farin-related bleeding, \I and those who are at higherrisk of
NSAID-induced GI bleeding."
There is an age-relateddecline in the warfarin dose re-
quired to produce the same anticoagulant effect.' 3,'5,81,82
The decrease with age in the free plasma warfarin concen-
tration required to produce a particular anticoagulant ef-
feet" and the greater reduction in the clotting factor syn-
thesis in older subjects" suggest that the reduced dosage
requirements are the result of increased target organ sensi-
tivity. Old age is also an independent risk factor for war-
farin-related bleeding.\1,85 In those aged 65 years or older,
concurrent use of NSAIDs and oral anticoagulants is asso-
ciated with a l3-fold increase in the risk of developing
hemorrhagic peptic ulcers." The elderly are also more
proneto NSAID-induced pepticulcers,JO,32
In general, liverdiseases are associated withan enhanced
anticoagulant response to warfarin." This increased sensi-
tivity is causedmore by impaired hepatic synthesis of vita-
min K-dependent clotting factors than by a reduced rate of
warfarin metabolism. Studies of patients with acute viral
hepatitis showed an increased anticoagulant response in
20% of the subjects, withoutany change in warfarin phar-
macokinetics."
In addition to smaller dosage requirements for warfar-
in," the incidence of upper GI hemorrhage is common
among Chinesesubjects." NSAIDs are itnplicated in 11 %
of Chinese patients admitted to acute medical wards with
this complication."
Other risk factors for warfarin-induced bleeding include
a history of GI bleeding, cerebrovascular disease, heart dis-
ease, renal insufficiency, hypertension, atrial fibrillation,
cancer, and severeanemia."
Summary
The following sections summarize the adverse drug re-
actions betweenwarfarin and NSAIDs.
SALICYLATES
• Aspirin has a direct hypoprothrombinemic effect only
if given in high doses (for a 70-kg man, the equivalent
of >6 g/d of aspirin given orally) or at serum salicylate
concentrations of morethan 300 mg/mLwithevidence
of acutetoxicity.
• In healthysubjects, aspirinin largerdosages (2-4 g/d)
potentiates the anticoagulant effect of warfarin and in-
creases the risk of bleedingin a dose-dependent man-
ner.
• In patients with prosthetic heart valves, concomitant
use of warfarin (INR 3.0-4.5) and low-dose aspirin
(100 mg/d) increases the risk of both minor and major
bleeding episodes.
• The risk of minor but not major or fatal bleeding
episodes was higher in patients treated with warfarin
plus aspirin 150 mg/d (lNR 2.2-2.8) than in those re-
ceivingwarfarin alone (INR 2.5-4.2).
• Excessive useof topical medicaments containing methyl
salicylate in patients receiving warfarin may result in
systemic absorption and bleeding episodes.
PHENYLBUTAZONE AND ITS ANALOGS
• In all healthy subjects and patients, phenylbutazone
and its analogs are expected to potentiate the anticoag-

Table 3. Case Reports of Anticoagulant Control in Warfarin-Treated Patients During

Addition or Withdrawal of Nonsteroidal Antiinflammatory Drugs"
DIAGNOSIS INDICATION
PATIENT (duration of (duration of CHANGES IN PT ANDIOR
NSAID REF. sex/age (y) warfarin therapy) NSAID therapy) WARFARIN DOSAGE

Indomethacin Self et al. (1975)" F/82 PTE, CHF, hypertension, gout (75-100 mg/d 21.7 to 42.2 s
CRF(5 d) for 5 d)
Piroxicam Rhodes et al. M/60 DVT, PTE, angina osteoarthritis of knee 1.6-1.7 to 1.3-1.4 s when NSAID stopped; 1.3-1.4
(1985f' (long-term) (20 mgld for 1-2 wk) to 1.6-1.7 s when NSAID added
Mallet and Cooper F/87 atrial fibrillation, stroke arm pain (20 mg/d) 16.5-18.1 to 24.9 s after 4 d and warfarin dose from
(1991)71 (long-term) 5 to 3.75 mg/d while taking NSAID; 22.7-24.1 to
13.5 s when taking warfarin 2.5 mg/d and NSAID
stopped
Sulindac Loftin and Vesell M/55 PTE, CRF (3 mo) Barter's syndrome PT ratio 2 to 2.5, a direct relationship between the
(1979)50 (200-400 mg bid for NSAID dose and the PT; warfarin dosage reduced
several days) accordingly
Carter (1979)" MI72 AVR, ankylosing arthritis (200 mg bid 20.3 to 26.0 s after 3 wk, warfarin dosage gradually
spondylosis (8 y) for 3-5 wk) reduced from 7.5 to 4.25 mg/d over 5 wk
Ross and Beeley M/56 AVR (5 y) rheumatic pains (100 INR 3.2 to 10.0
(1979)68 bid for 5 d)

AVR = aortic valve replacement; CHF = congestive heart failure; CRF = chronic renal failure; DVT = deep-vein thrombosis; INR = international normal-
ized ratio; NSAID = nonsteroidal antiinflammatory drug; PT = prothrombin time; PTE = pulmonary thromboembolism.
"Refer to text for reports involving topical methyl salicylate therapy.

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ulant effect of warfarin by substantially inhibiting S-
warfarin while enhancing the elimination of R-war-
farin.
• Apazone has the greatest risk of inducing bleeding
peptic ulcers.
OTHER NSAIDS
• All NSAIDs have antiplatelet effects that result in a
prolonged bleeding time. These effects are less pro-
nounced in NSAIDs not containing aspirin than in as-
pirin.
• In therapeutic doses, NSAIDs not containing aspirin
alone do not have an effect on clotting factor activity.
• In healthy subjects, the following NSAIDs have not
been shown to enhance the anticoagulant effect of
warfarin during combined use: diflunisal, etodolac, fen-
bufen, ibuprofen, indomethacin, ketorolac, lomoxicam,
nabumetone, naproxen, sulindac, and tenoxicam.
• In healthy subjects, mefenamic acid has been shown to
enhance the anticoagulant effect of warfarin.
• In healthy subjects, following a period of coadminis-
tration with warfarin, a loss of anticoagulant control is
seen after the following NSAIDs are withdrawn: diflu-
nisal and lomoxicam.
• In patients receiving long-term warfarin therapy, the
following NSAIDs have not been shown to enhance
the anticoagulant effect of warfarin during combined
use: ibuprofen, nabumetone, and nimesulide.
• During studies of interactions between NSAIDs and
warfarin, bleeding complications have been reported
in healthy subjects (mefenamic acid, naproxen) or in
patients (ibuprofen) even in the absence of a change in
PT.
• There are isolated reports of bleeding complications
and prolongation of PT when the following NSAIDs
are given to patients taking long-term warfarin thera-
py: indomethacin, ketoprofen, sulindac, and tolmetin.
• There are isolated reports of loss of anticoagulant con-
trol when the following NSAIDs are given to or with-
drawn from patients taking long-term warfarin thera-
py: ibuprofen, indomethacin, piroxicam, and sulindac.
• The incidence of hospitalizations for hemorrhagic pep-
tic ulcers in patients aged 65 years or older taking both
warfarin and NSAIDs other than aspirin was 26.3 per
!Ooo person-years, about 13 times that of patients not
taking either drug.
• The use of the following NSAIDs is associated with a
higher risk of bleeding peptic ulcers: piroxicam in
adults, and ketoprofen in subjects aged 60 years or
older.
Recommendations
Based on the data reviewed here, the following recom-
mendations can be made.
• NSAIDs should be avoided, as much as possible, in
patients taking warfarin. This is particularly important
in those who are expected to be more susceptible to
the interactions between the 2 drugs and the adverse
sequelae.
• In patients receiving warfarin, phenylbutazone and its
analogs, or high dosages of aspirin (2-4 g/d), exces-
The Annals ofPhannacotherapy •
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Warfarin-NSAID Interactions
sive use of topical methyl salicylate and mefenamic
acid should be avoided. Phenylbutazone and its ana-
logs have already been removed from use in many
countries because of their other toxicities.
• In patients receiving warfarin, NSAIDs that are known
to be associated with a higher risk of bleeding peptic
ulcers should be avoided.
• In patients receiving warfarin, NSAIDs, if needed,
should be given in lower dosages where feasible and
introduced slowly. PT should be monitored closely, es-
pecially during the first 2 weeks of therapy. Patients
also should be monitored closely for any bleeding
complications. When NSAIDs are stopped, be aware
of the potential for loss of anticoagulant control. ~
References
1. Serlin Ml, Breckenridge AM. Drug interactions with warfarin. Drugs
1983;25:61Q..20.
2. O'Reilly RA. Warfarin metabolismand drug-drug interactions. Adv Exp
Med BioI1987;214:205-12.
3. Buckley NA, Dawson AH. Drug interactionswith warfarin.Med 1 Aust
1992;57:479-83.
4. Freedman MD, Olatidoye AG. Clinically significant drug interactions
with the oral anticoagulants. Drug Saf 1994;I0:381-94.
5. O'Callaghan lW, Thompson RN, RussellAS. Combining NSAIDs with
anticoagulants; yes and no. Can Med Assoc 11984;131:857-9.
6. Eble IN, West BD, Link KP. A comparison of the isomers of warfarin.
BiochemPharmacoI1966;15:1003-6.
7. Hewick DS, McEwan 1. Plasma half-lives,plasma metabolitesand anti-
coagulant efficacies of the enantiomers of warfarin in man. 1 Pharm
PharmacoI1973;25:458-65.
8. Holford NHG. Clinical pharmacokinetics and pharmacodynamics of
warfarin. Understanding the dose-effect relationship. Clin Pharma-
cokinet 1986;11:483-504.
9. Saour 1, Gallus A. Warfarin: is it time to reduce target ranges again?
Aust N Z 1 Moo 1993;23:692-6.
10. Landefeld CS, Goldman L. Major bleeding in outpatients treated with
warfarin:incidence and predictionby factors known at the start of out-
patienttherapy.Am 1 Med 1989;87:144-52.
11. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epi-
demiology,prediction,and prevention. Am 1 Med 1993;95:315-28.
12. Routledge PA. Clinical pharmacology and the art of bespoke prescrib-
ing. Br 1 Clin PharmacoI1988;26:339-45.
13. Routledge PA, Chapman PH, Davies DM, Rawlins MD. Factors affect-
ing warfarin requirements. A prospective population study. Eur 1 Clin
PharmacoI1979;15:319-22.
14. BjornssonTO. Anticoagulants. In: Williams RL, Brater DC, Mordenti1,
eds. Rational therapeutics. A clinical pharmacologic guide for the
health professional. New York: Marcel Dekker, 1990:541-77.
15. Chan TYK, Tsoi WC, CritchleylAlli. The determinantsof warfarinre-
quirements in Chinese patients. PharmacoepidemiolDrug Saf 1992;1:
281-2.
16. Pullar T, Capell HA. Interaction between oral anti-coagulantdrugs and
non-steroidal anti-inflammatory agents: a review.Scott Med 11983;28:
42-7.
17. Tonkin AL, Wing LMH. Interactions of non-steroidal anti-inflammatory
drugs. BaillieresClin Rheumatol 1988;2:455-83.
18. Johnson AG, SeidemanP, Day RO. Adversedrug interactions with non-
steroidalanti-inflammatory drugs (NSAIDs): recognition, management
and avoidance. Drug Saf 1993;8:99-127.
19. Johnson AG, Seidemann P, Day RO. NSAID-related adverse drug inter-
actions with clinical relevance. An update. Int 1 Clin Pharmacol Ther
1994;32:509-32.
20. Quick AJ, Clesceri L. Influence of acetylsalicylicacid and salicylamide
on the coagulationof blood.1 PharmacolExp Ther 1960;128:95-8.
21. Rothschild BM. Hematologic perturbations associated with salicylate.
Clin PharmacolTher 1979;26:145-52.
22. Diana Fl, Veronich K, Kapoor AL. Bindingof non-steroidal anti-inflam-
matory agents and their effect on binding of racemic warfarin and its
enantiomersto human serum albumin.1 Pharm Sci 1989;78: 195-9.
1995 December. Volume 29 • 1281
23. Mackichan 11.Protein binding drug displacement interactions-fact or
fiction?Clin Phannacokinet 1989;16:65-73.
24. BanfieldC, O'Reilly R, Chan E, Rowland M. Phenylbutazone-warfarin
interaction in man: further stereochemical and metabolic considera-
tions. Br 1 Clin PhannacoI1983;16:669-75.
25., Roth Gl, Majerus PW. The mechanism of the effects of aspirin on hu-
man platelets. 1. Acetylation of a particular fraction protein.1 Clin In-
vest 1975;56:624-32.
26. McQueen EG, Facoory B, Faed 1M. Non-steroidal anti-inflammatory
drugs and plateletfunction. N Z Med 1 1986;99:358-60.
27. Shorr RI, Ray WA, Daugherty lR, Griffin MR. Concurrent use of non-
steroidalanti-inflammatory drugs and oral anticoagulants placeselderly
persons at high risk for hemorrhagic peptic ulcer disease. Arch Intern
Med 1993;153:1665-70.
28. Hurlen M, Erikssen 1, Smith P, Arnesen H, Rollag A. Comparison of
bleeding complications of warfarin and warfarin plus acetylsalicylic
acid: a study in 3166 out-patients. 1 Intern Med 1994;236:299-304.
29. Hawkey C1. Non-steroidal anti-inflammatory drugs and peptic ulcers:
facts and figuresmultiply,but do they add up? BMJI990;300:278-84.
30. Langman MJS, Brooks P, Hawkey Cl, Silverstein F, Yeomans N. Non-
steroidalanti-inflammatory drug associatedulcer:epidemiology,causa-
tion and treatment.1 Gastroenterol Hepatol 1991;6:442-9.
31. LangmanMJS, Weill, WainwrightP, Lawson DH, RawlinsMD, Logan
RFA, et al. Risks of bleeding peptic ulcer associated with individual
non-steroidal anti-inflammatory drugs. Lancet 1994;343: 1075-8.
32. FriesIF, WilliamsCA, Bloch DA, Michel BA. Nonsteroidal anti-inflam-
matory drug-associatedgastropathy: incidenceand risk factor models.
AmlMed 1991;91:213-22.
33. Holmes EL. Pharmacologyof the fenamates: IV. Toleration by normal
human subjects.Ann Phys Med 1966;8(suppl):36-49.
34. O'Reilly RA, Sahud MA, Aggeler PM. Impact of aspirin and chlorthali-
done on the pharmacodynamics of oral anticoagulant drugs in man.
Ann N Y Acad Sci 1971;1'79: 173-86.
35. Serlin MJ, Mossman S, Sibeon RG, Tempero KF, Breckenridge AM. In-
teraction between diflunisal and warfarin. Clin Pharmacol Ther 1980;
28:493-8.
36. Ermer lC, Hicks DR, Wheeler SC, Kraml M, lusko W1. Concomitant
etodolac affects neither the unbound clearance nor the pharmacologic
effect of warfarin. Clin Pharrnacol Ther 1994;55:305-16.
37. SavitskyIP, TerzakisT, Bina P, ChiccarelliF, Haynes1. Fenbufen-war-
farin interaction in healthy volunteers (abstract). Clin Pharmacol Ther
1980;27:284.
38. Goncalves L. Influence of ibuprofen on haemostasis in patients on anti-
coagulanttherapy.1 Int Med Res 1973;1:180-3.
39. Penner lA, Abbrecht PH. Lack of interaction between ibuprofen and
warfarin.Curr Ther Res 1975;18:862-71.
40. SchulmanS, Henriksson K Interaction of ibuprofenand warfarinon pri-
mary haemostasis. Br 1 RheumatoI1989;28:46-9.
41. Vesell ES, Passananti GT,lohnson AO. Failure of indomethacin and
warfarin to interact in normal human volunteers. 1 Clin Pharmacol
1975;15:486-95.
42. Mieszczak C, Winther K. Lack of interaction of ketoprofen with war-
farin. Eur1 Clin Phannacoll993;44:205-6.
43. Toon S, Holt BL, Mullins FGP, Bullingham R, Aarons L, Rowland M.
Investigations into the potential effects of multiple dose ketorolac on
the pharmacokinetics and pharmacodynamics of racemic warfarin.Br 1
Clin Pharmacoll990;30:743-50.
44. Ravic M, Johnson A, Turner P, Ferber HP. A study of the interaction be-
tween lornoxicamand warfarin in healthy volunteers. Hum Exp Toxi-
col 1990;9:413-4.
45. FitzgeraldDE. Double-blindstudyto establishwhetherthere is any inter-
action between nabumetone and warfarin in healthy male volunteers.
In: Panayi GS, Price Jl), Rotman H, eds. Nabumetone,a novel anti-in-
flammatory. Vol 69. London:Royal Societyof Medicine, 1985:47-52.
46. HillemanDE, MohiuddinSM, LucasBD Jr. Nonsteroidal antiinflamma-
tory drug use in patients receiving warfarin:emphasis on nabumetone.
Am 1 Med 1993;95(suppI2A):S30-4.
47. SlatteryIT, Levy G,lain A, McMahonFG. Effectofnaproxen on the ki-
neticsof eliminationand anticoagulantactivityof a single dose of war-
farin.Clin Phannacol Ther 1979;25:51-60.
48. lain A, McMahon FG, Slattery IT, Levy G. Effect of naproxen on the
steady-stateserum concentration and anticoagulant activityof warfarin.
Clin Phannacol Ther 1979;25:61-6.
49. Auteri A, Bruni F, Blardi P, Di Renzo M, Pasqui AL, Saletti M, et al.
1282 • The AnnalsofPharmacotherapy • /995 December. Volume 29
Downloaded from aop.sagepub.com at CORNELL UNIV on July 27, 2016
Clinical study on pharmacological interactionbetween nimesulide and
warfarin.Intl Clin Phannacol Res 1991;11:267-70.
50. Loftin IP, Vesell ES. Interaction between sulindac and warfarin: differ-
ent results in normal subjects and in an unusual patient with a potassi-
um-losingrenal tubulardefect.1 Clin Phannacol 1979;19:733-42.
51. Eichler HG,lung M, Kyrle PA, Rotter M, Korn A. Absence of interac-
tion between tenoxicam and warfarin. Eur 1 Clin Pharmacol 1992;42:
227-9.
52. Koch-Weser1, Sellers EM. Drug interactionswith coumarin anticoagu-
lants. N EnglJ Med 1971;285:547-58.
53. Fox SL. Potentiating of anticoagulants caused by pyrazole compounds.
lAMA 1964;188:320-1.
54. Eisen M1. Combined effect of sodium warfarin and phenylbutazone.
lAMA 1964;189;64-5.
55. Aggeler PM, O'Reilly RA, Leong L, Kowitz PE. Potentiationof antico-
agulanteffect of warfarinby phenylbutazone. N Eng11Med 1967;276:
496-501.
56. BuIll, MacKinnon 1. Phenylbutazoneand anticoagulantcontrol. Practi-
tioner 1975;215:767-9.
57. Hobbs CB, Miller AL, Thornley lH. Potentiationof anticoagulantthera-
py by oxyphenylbutazone: a probable case. Postgrad Med 1 1965;41:
563-5.
58. Powell-lackson PRo Interactionbetween azapropazone and warfarin. Br
Med 11977;1:1193-4.
59. Green AE, Hort IF, Korn HET, Leach H. Potentiation of warfarin by
azapropazone (letter).Br Med j 1977;I:1532.
60. Win N, Mitchell DC,lones PAE, French EA. Azapropazone and war-
farin. BMl 1991 ;302:969-70.
61. Thompson PL, Serjeant C. Potentially serious interaction of warfarin
with sulfinpyrazone (letter).Med 1 AustI981;1:41.
62. O'Reilly RA. Stereoselectiveinteractionof sulfinpyrazone with racemic
warfarin and its separated enantiomorphs in mart, Circulation 1982;
65:202-7.
63. BeeleyL. Azapropazoneand warfarin(letter).BMJI991;302:1341.
64. lust ice lL, Kline SS. Analgesics and warfarin. A case that brings up
questionsand cautions. PostgradMed 1988;83:217-8,220.
65. Koch-Weser1. Hemorrhagicreactions and drug interactionsin 500 war-
farin-treated patients(abstract). Clin Phannacol Ther 1973;14:139.
66. Chan TYK, Lui SF, Chung SY, Luk S, CritchleylA1H. Adverse interac-
tion between warfarinand indomethacin. Drug Saf 1994;10:267-9.
67. Flessner MF, Knight H. Prolongation of prothrombin time and severe
gastrointestinal bleeding associatedwith combined use of warfarinand
ketoprofen(letter).lAMA 1988;259:353.
68. Ross lRY, Beeley L. Sulindac, prothrombin time, and anticoagulants
(letter).Lancet 1979;2: 1075.
69. Thatcher 1, George D. Retropharyngea1 hematoma as a new cause of
acute upper airway obstruction in rheumatoid arthritis. 1 Rheumatol
1987;14:1172-3.
70. Koren IF, Cochran DL,lanes RL. Tolmetin-warfarin interaction (letter).
Am 1 Med 1987;82: 1278-9.
71. Yip ASB, Chow WH, Tai YT, Cheung KL. Adverse effect of topical
methylsalicy1ateointment on warfarin anticoagulation: an unrecog-
nized potentialhazard. PostgradMed 11990;66:367-9.
72. Littleton F lr. Warfarin and topical salicy1ates (letter).lAMA 1990;263:
2888.
73. Tam LS, Chan TYK, Leung WK, CritchleyJAlH. Warfarin interactions
with Chinese traditional medicines: danshen and methyl salicylate
medicatedoil. Aust N Z J Med 1995;25:258.
74. Lo ACT, Chan K, YeunglHK, Woo KS. The effects of danshen (Salvia
miltiorrhiza) on pharmacokinetics and pharmacodynamicsof warfarin
in rats. Eur J Drug Metab Phannacokinetl992;I7:257-62.
75. Turpie AG, Gent M, LaupacisA, Latour Y, GunstensenJ, Basile F, et al.
A comparison of aspirin and placebo in patients treated with warfarin
after heart-valvereplacement. N Engl J Med 1993;329:524-9.
76. Self TH, Evans WE, FergusonT. Drug enhancementof warfarinactivity
(letter).Lancet 1975;2:557-8.
77. Rhodes RS, Rhodes PJ, Klein C, Sintek CD. A warfarin-piroxicam in-
teraction. Drug IntellClin Phann 1985;19:556-8.
78. Mallet L, Cooper JW. Prolongationof prothrombintime with the use of
piroxicamand warfarin. Can J Hosp Pharm 1991 ;44:93-4.
79. Carter SA. Potentialeffect of sulindac on response of prothrombin-time
to oral anticoagulants (letter).Lancet 1979;2:698-9.
80. RodriguezLAG, Jick H. Risk of upper gastrointestinal bleedingand per-

foration associated with individualnon-steroidalanti-inflammatory
drugs. Lancet1994;343:769-72.
81. RedwoodM, Taylor C, Bain Bl, Matthews IH. The association of age
withdosage requirement for warfarin. Age Ageing 1991;20:217-20.
82. lames AH, Britt RP, RaskinoCL, Thompson sa. Factorsaffecting the
maintenance doseof warfarin. 1 ClinPathoI1992;45:704-6.
83. Routledge PA,Chapman PH, Davies DM,Rawlins MD.Phannacokinet-
ics and pharmacodynamics of warfarin at steady state.Br 1 Clin Phar-
macoI1979;8:243-7.
84. Shepherd AMM, Hewick DS,Moreland TA, Stevenson IH. Ageas a de-
terminant of sensitivity to warfarin. Br 1 Clin PhannacoI1977;4:315-
20.
85. HylekEM,SingerDE. Riskfactors for intracranial hemorrhage in outpa-
tientstakingwarfarin. AnnInternMed 1994;120:897-902.
86. Chan TYK. Recognizing increased sensitivity to warfarinin liver dys-
function secondary to congestive heart failure. Pharmacoepidemiol
DrugSaf 1995 (in press).
87. Williams RL, ScharyWL, Blaschke TF, MeffinPI, MelmonKL, Row-
landM. Influence of acuteviralhepatitis on disposition and pharmaco-
logiceffectof warfarin. ClinPhannacol Ther 1976;20:90-7.
88. ChanTYK,Critchley lAlli, ChanlCN, Tomlinson B, ChanMTV.Dis-
easeprofiles in Chinese in HongKong: an analysis of theprimary diag-
nosesin 561 acutehospital medical admissions. Southeast Asian 1Trop
Med Public Health 1993;24:766-8.
89. ChanTYK,ChanlCN, Tomlinson B, Critchley lAlli. Adverse reactions
to drugsas a causeof admissions to a general teaching hospital in Hong
Kong. DrugSaf 1992;7:235-40.
REsUME
OBJECTIF: Passer en revue les mecanismes et la signification cliniquede
I'interaction medicamenteuseimpliquantla warfarineet les
antiinflammatoires non steroidiens(AINS) et dieter une ligne de
conduite afin d' eviter cette interactionautant que possible.
The AnnalsofPharmacotherapy • 1995 December, Volume 29 •
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Warfarin-NSAID Interactions
REVUE DEL1'I'TERATURE: Les etudes traitant des interactionsentre la
warfarine et les AINS ou les rapports d'interactions ont ete identifies a
partir de la banque de donnees MEDLINE (1976 ace jour) ou apartir
des listes de referencescitees dans les articlespertinents.
SELEcnON DESETUDES: L'auteur a considers tous les articles pour les
inclure acette revue.
REsUME: Tous les AINS peuvent prolonger Ie temps de saignement en
inhibant la fonction plaquettaire. L'aspirine, adose elevee, possede un
effet bypoprothrombinemiant direct. La phenylbutazoneet les
substancesanalogues augmentent I'action de la warfarine par
!'inhibition du metabolisme hepatique de celle-ci. L'acidemefenamique
augmente aussi l'effet anticoagulantde la warfarine mais par un
mecanismeinconnu. La significationclinique du deplacementde la
warfarine de ses sites de liaison aux proteines plasmatiquespar les AINS
a ere exageree, Par contre, une interactionsignificativeest susceptiblede
se produire en presence de concentrations elevees d' AINS chez des
patientsqui ont un ralentissementde l'elirnination de la warfarine (e.g.,
patients atteints d'insuffisance cardiaque severe ou dont la fonction
hepatiqueest alteree), Finalement, les AINS peuvent causer un
saig'nement gastrointestinalqui peut etre plus severe si la warfarine est
administreeen concomitance.
CONCLUSIONS: L'administration concomitantede la warfarine et des
AINS devrait generalementetre evitee acause du risque accru de
saignementchez ces patients. Si un AINS est requis chez un patient qui
recoit de la warfarine, les medicaments suivantsdevraient etre evites: la
phenylbutazone(et substancesanalogues), I'aspirine adose elevee,
Pacide mefenamique,l'utilisation topique excessive de salicylatede
methyle et les AINS qui sont associes aun risque plus elevee de
saignementen presence d'ulceres peptiques(piroxicamchez l'adulte et
ketoprofenechez la personne agee). Enfin, une surveillanceetroite de
l' anticoagulotherapie et des complications hemorragiques devrait etre
effectuee dans de tels cas.
MICHELE PLANlE
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