The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy

STUDY OBJECTIVE: To determine whether an interaction exists between acetaminophen and warfarin that alters the international normalized ratio (INR). DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Anticoagulation clinic at a Veterans Affairs Medical Center. PATIENTS: Thirty-six adult patients receiving warfarin with stable INRs, defined as two consecutive INRs at least 3 weeks apart that were within the therapeutic range. INTERVENTION: Patients were randomly assigned to receive acetaminophen 1 g twice/day along with matching placebo twice/day (12 patients), acetaminophen 1 g 4 times/day (12 patients), or matching placebo 4 times/day (12 patients) for 4 weeks. MEASUREMENTS AND MAIN RESULTS: The primary end point was the difference in mean INR between groups at weekly intervals. Secondary end points were the percentages of patients in each group with supratherapeutic (INR > or = 0.3 above the upper limit of their therapeutic range) or subtherapeutic (INR > or = 0.2 or 0.3 below the lower limit of their respective therapeutic range of 2.0-3.0 or 2.5-3.5) INRs, and the difference in mean serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels between groups at biweekly intervals. Slow enrollment and a preliminary observation that 15 patients experienced an elevated INR prompted early termination of the study. At week 2, the group receiving acetaminophen 2 g/day had a significantly higher mean INR versus the placebo group (p=0.01). At weeks 1, 2, and 3, the acetaminophen 4-g/day group had significantly higher mean INRs compared with those in the placebo group (p=0.04, p=0.01, p=0.01, respectively). In addition, 13 (54%) of 24 patients in the acetaminophen groups combined exceeded the upper limit of their therapeutic range by 0.3 or greater compared with only 2 (17%) of 12 patients in the placebo group. No statistically significant differences in serum ALT or AST levels between either acetaminophen group versus the placebo group were found at week 4; however, there was a statistically significant increase in mean ALT level at week 2 in the acetaminophen 4-g/day group versus the placebo group. CONCLUSION: These findings support the existence of a clinically significant interaction between warfarin and daily use of acetaminophen 2-4 g, necessitating close monitoring of patients who receive this drug combination. Whether this interaction occurs when acetaminophen is taken in lower doses or is used sporadically requires further study.