Brief Alerts

Warfarin and Acetaminophen

Source: Hylek EM, et al. JAMA 1998;279:657-662.

Acetaminophen has always been considered the safe nonsteriodal anti-inflammatory drug (NSAID), but new evidence suggests it is an underrecognized cause of oral anticoagulation insatiability. Hylek and associates performed a case-controlled study of patients on warfarin and compared 93 patients with international normalized ratios of prothrombin time (INRs) longer than 6.0 to 196 patients with INRs in the therapeutic range (1.7-3.3). All patients were interviewed within 24 hours of their INR determination. Independent risk factors for an INR longer than 6.0 included: advanced malignancy (odds ratio 16.2; P < 0.004); new medication known to interfere with warfarin (OR 8.5; P < 0.001); taking more warfarin than prescribed (OR 8.1; P = 0.002); decreased oral intake (OR 3.6; P = 0.01); and acute diarrheal illness (OR 3.5; P = 0.007). Interestingly, acetaminophen use was also an independent risk factor once the dose threshold of seven, 325 mg tablets/week was exceeded.

Increased consumption of foods high in vitamin K (OR 0.7; P = 0.003) or habitual, moderate alcohol consumption (OR 0.2; P = 0.01) decreased the risk of an INR greater than 6.0. Hylek et al conclude that modification of these clinically important risk factors, including acetaminophen use, should reduce the incidence of dangerously high oral anticoagulation levels.

The major limitation to this type of study is that the interviewers and subjects were not blinded to the INR levels for safety reasons, and the results depend on patient recall. However, the dose response relationship with acetaminophen was impressive, and the interaction is biologically plausible because both agents are metabolized in the liver by the P-450 system. Also, this study confirms case reports describing a warfarin, acetaminophen interaction. Thus, patients should be warned about taking more than six acetaminophen tablets in one week. -mhc