Department of Rheumatology, Dijon University Hospital and University of Burgundy, Dijon, France
Correspondence to: J. F. Maillefert, Department of Rheumatology, Hôpital Général, 3 rue du Faubourg Raines, 21000 Dijon, France. E-mail: jean-francis.maillefert{at}chu-dijon.fr
SIR, Paracetamol is a well-tolerated analgesic that is frequently used as a first-line drug in numerous chronic painful diseases, such as osteoarthritis. Paracetamol interacts with certain drugs, including warfarin and some other oral anticoagulant drugs, and can increase prothrombin time. Thus, it has been recommended that the prothrombin time should be carefully monitored in patients taking warfarin sodium who subsequently begin high-dose paracetamol treatment [1]. In spite of this, many warfarin-treated patients are cotreated with paracetamol-containing products [2]. Two main hypotheses can be put forward to explain such a discrepancy. First, some physicians might not be aware of the potential interaction between these drugs as the potential interaction is not reported in some drug dictionaries, such as the French Vidal drug dictionary. Secondly, as the changes in the anticoagulant effect have generally been of limited clinical significance, physicians might consider the combination to be safe. However, physicians should be aware that paracetamol can lead to clinically significant anticoagulant instability. We report here a case of this under-recognized side-effect in a patient receiving fluindione for atrial fibrillation, for whom the anticoagulation response, usually well controlled, was disturbed by paracetamol therapy.
A 72-yr-old man was hospitalized in 2004 for a 2-day history of spontaneous skin haematomas and gingival bleeding. His medical history included diabetes mellitus, blood hypertension and a stroke due to atrial fibrillation in 2001. He had been treated with fluindione for 3 yr. The coagulation was stabilized and the daily dose of fluindione had been unchanged during the 6 months preceding hospitalization (15 mg). The international normalized ratio (INR) had last been determined 2 weeks earlier, with a satisfactory result of 2.3. Compliance with fluindione treatment was correct and no error in anticoagulant dose was detected. Alcohol intake was light to moderate and there were no biological signs of liver disease. On admission, physical examination revealed haematoma of the left arm, right forearm and right thigh. Oral examination showed gingival bleeding and haemorrhagic bubbles. On laboratory examination, the INR was 8. There was a major decrease in serum vitamin K-dependent coagulation factors, whereas other coagulation factors remained within normal limits. No anaemia or thrombopenia was noted and renal function was normal. Because the patient complained of an anterior pain of the right thigh, an abdominal CT scan was performed; it did not reveal any psoas haematoma.
A diagnosis of bleeding due to severe hypocoagulation was proposed. The search for causes of such severe hypocoagulation did not reveal any acute diarrhoea and there had been no change in vitamin K intake or voluntary diet. The patient's regular treatments (glimepiride, ramipril and digoxin) were not known to interact with anticoagulant therapy and the daily doses had not been changed recently. No medications had been introduced recently, except for paracetamol, which had been prescribed at the maximal dose (4 g per day) 10 days prior to hospitalization for knee pain. Paracetamol was withdrawn and intravenous vitamin K supplementation and vitamin K-dependent coagulation factors were given. The INR and prothrombin time returned rapidly to normal levels. After 6 days of hospitalization, the patient was discharged.
In our opinion, this unexpected elevation of the INR with haemorrhagic complications in a patient taking oral anticoagulants was due to an interaction between the usual anticoagulant treatment and paracetamol. The recent history was suggestive of such an interaction. No intake of another drug which could potentially interact with anticoagulants was found, and there were no other causes, such as a decrease in vitamin K intake, an acute illness or a change in anticoagulant dosage. Moreover, previous reports have suggested that paracetamol can sometimes interact with oral anticoagulants and lead to severe morbidity. In a casecontrol study evaluating 289 patients treated with warfarin, including 93 with excessive anticoagulation (INR >6) compared with 196 controls with INR between 2 and 3, the consumption of paracetamol was significantly higher in patients with excessive anticoagulation, independently of other confounding risk factors [3]. Moreover, a dose-dependent relationship was observed between the weekly intake of paracetamol and the risk of anticoagulation instability. In a double-blind crossover study comparing paracetamol (4 g/day) and placebo in patients treated with stable warfarin doses, an increase of 100% or more in the prothrombin time was observed in one-third of the paracetamol-treated patients [4]. This effect was detected after 1 week of paracetamol intake and was maximal during the second week, with great interpatient variability. In the present observation, the oral anticoagulant was fluindione, while most studies have been conducted using warfarin. However, it is likely that the mechanism of paracetamol-induced increased INR is the same for both drugsprobably a decrease in catabolism.
Numerous arthritic patients are cotreated with paracetamol and oral anticoagulants. Regarding the frequency of coprescription, in most cases the potential biological interaction does not lead to any clinical adverse effect. However, the present observation shows that this combination is not as safe as generally believed and can sometimes induce life-threatening hypocoagulation, and suggests that INR monitoring should be intensified in patients treated with oral anticoagulants to whom paracetamol is given.
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No conflict of interest has been declared by the authors.
References
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