CORRESPONDENCE

Adverse Interaction Between Warfarin and Indomethacin

The title given in the case report by Chan et al.[1] implies that indeed an adverse interaction has oc­curred. This is unfortunate, because the evidence for an effect of indomethacin on prothrombin ratio in the presence of warfarin is, at best, quite circum­stantial. The consequence is that the interaction and its proposed mechanism will gain credence and a life of its own in drug interaction data bases and eventually textbooks.

On the patient's second admission with sponta­neous bruising and gross haematuria his interna­tional normalised ratio (INR) was found to be 3.6, having increased from 3.4 in the interim between his first and second admission which led to his war­farin being reduced from 3 to 2.5 mg/day.

The INR increase was not great and such an in­crease is seen commonly without accompanying bleeding. There are a number of possibilities apart from concurrent indomethacin that could explain the increase in his INR. He was hypertensive and had a deep vein thrombosis (with a risk of pulmo­nary embolus), and may have had a degree of right heart failure and associated liver congestion, which is known to be associated with greater sensitivity to warfarinJ2] It would have been safer to accept the verdict 'not proven', given the details of the case.

Although we agree that it is well established that there is an important interaction between the non­steroidal anti-inflammatory drugs (NSAIDs), in­cluding aspirin, and warfarin, this is largely due to

Drug Safety 11 (3): 213-214. 1994 0114-5916/94/0009-o213/S01.00/0

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a pharmacodynamic interaction based upon the platelet inhibitory effects of the NSAID, the anti­coagulant effect of warfarin and the potential for gastrointestinal damage from NSAIDs.[3] We would submit that the first proposed mechanism for this interaction, namely displacement of warfa­rin from plasma protein binding sites, is now not accepted as a potential mechanismJ4] Additionally, there are no data to suggest a metabolic interaction such as is seen with azapropazone and phenyl­butazone and warfarin[5,6] and, as pointed out by the authors, the only study examining the combi­nation of drugs systematically showed no pharma­cokinetic interaction. [7]

Although we agree that careful monitoring of patients who are commenced on indomethacin or any other NSAID who happen also to be on warfa­rin is appropriate, we do not believe this case report is 'strongly suggestive of a clinically significant interaction between the two drugs'.

Incidentally, it is noted that the patient in this report had been taking allopurinol but this was stopped during the first admission for treatment of deep venous thrombosis because he had an acute attack of gout. We wonder if allopurinol was re­commenced during the 10 days post admission I? If so, allopurinol as a metabolic inhibitor has been noted to be associated with increases in warfarin effect on the INR.[8]

RICHARD DAY DAVID QUINN

St Vincent's Hospital Sydney Australia

References I. Chan TYK, Yui SF, Chung SY, et aI. Adverse interaction be­

tween warfarin and indomethacin. Drug Saf 1994; 10: 267-9 2. O'Reilly RA, Aggeler PM. Determinants of response to oral

anticoagulant drugs in man. Pharmacol Rev 1970; 22: 35-96 3. Schulman S, Henrikson K. Interaction of ibuprofen and warfa­

rin on primary haemostasis. Br J Rheumatol1989; 28: 46-9 4. Rolan PE. Plasma protein binding displacement interactions -

214

why are they still regarded as clinically important? Br J Clin Pharmacol 1994;37: 125-8

5. O'Callaghan JW, Thompson RN, Russell RS. Combining NSAIDs with anticoagulants: yes and no. Can Med Assoc J 1984; 131: 857-9

6. Tonkin AI, Wing LMH. Interactions of non steroidal anti inflam­matory drugs. Baillieres Clin Rheum 1988; 2: 455-83

7. Vessel ES, Passananti GT, Johnson AO. Failure of indomethacin and warfarin to interact in normal human volunteers. Clin Pharmacol 1975; 15:486-95

8. Barry M, Feely J. Allopurinol influences aminophenazone elim­ination. Clin Pharmacokinet 1990; 19: 167-9

The authors reply: We wish to thank Professor Day and Dr Quinn

for their interest in our report.£l] In our patient, there was no evidence of right

heart failure or impaired liver function in both hos­pital admissions or during subsequent follow-up in the outpatient clinic. Allopurinol would not have been responsible as it was stopped during the first admission, and only restarted when the patient was discharged from hospital after the second admis­sion.

The absence of other precipitating factors and the temporal relationship between the administra­tion of indomethacin and the onset of bleeding are strongly suggestive of an adverse interaction be­tween indomethacin and warfarin. Thus, despite the warfarin dose being reduced when the INR was 3.4, from 3 to 2.5 mg/day, with the concurrent ad­ministration of indomethacin the INR rose further to 3.6. Subsequently, without indomethacin, a maintenance warfarin dosage of 2.5 mg/day gave a stable INR of 2.0 to 2.5. It is possible that the con­comitant anti platelet effects of indomethacin and the prolongation of his INR up to 3.6 for more than 7 days had led to bleeding. Chinese patients, whose

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Day et al.

warfarin requirements are known to be much less than Caucasians,[2] may be particularly at risk of bleeding when indomethacin and warfarin are given concurrently and when their INR is elevated for a prolonged period.

As with those cases described by othersp-5] our case serves to highlight the potential interaction between indomethacin and warfarin, and the im­portance of closely monitoring the prothrombin time in these patients. It is now generally accepted that the anticoagulant effect of warfarin may pos­sibly be enhanced by NSAIDs,£6] although we agree that displacement from plasma protein bind­ing sites does not have the importance that was once thought.

THOMAS Y.K. CHAN

JULIAN A.J.H. CRITCHLEY

Department of Clinical Pharmacology The Chinese University of Hong Kong Prince of Wales Hospital Shatin, N.T., Hong Kong

References 1. Chan TYK, Lui SF, Chung SY, et al. Adverse interaction be­

tween warfarin and indomethacin. Drug Saf 1994; 10: 267-9 2. Chan TYK, Tsoi WC, Critchley JAJH. The determinants of war­

farin requirements in Chinese patients. Pharmacoepidemiol Drug Saf 1992; 1: 281-2

3. Hoffbrand BI, Kininmonth DA. Potentiation of anticoagulants. BMJ 1967; 2: 838-9

4. Koch-Weser J. Hemorrhagic reactions and drug interactions in 500 warfarin treated patients. Clin Pharmacol Ther 1973; 14: 139

5. SelfTH, Evans WE, Ferguson T. Drug enhancement of warfarin activity. Lancet 1975; 2: 557

6. British National Formulary. London: British Medical Associa­tion and the Royal Pharmaceutical Society of Great Britain, 1993: No. 25, 509

Drug Safety 11 (3) 1994