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 ≥ 0.3 above the upper limit of their therapeutic range) or subtherapeutic (INR ≥ 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.