title: The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy.
abstract: OBJECTIVE
  To determine whether an interaction exists between acetaminophen and warfarin that alters the international normalized ratio (INR).
  
  
  METHODS
  Prospective, randomized, double-blind, placebo-controlled trial.
  
  
  METHODS
  Anticoagulation clinic at a Veterans Affairs Medical Center.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Section of Clinical Pharmacy, Patient Support Service, Department of Veterans Affairs Medical Center, West Palm Beach, Florida 33410-6400, USA. David.Parra@med.va.gov
authors.forename: David
authors.initials: D
authors.lastname: Parra
authors.forename: Nick P
authors.initials: NP
authors.lastname: Beckey
authors.forename: Gary R
authors.initials: GR
authors.lastname: Stevens
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000925:Anticoagulants / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood / Q000187:drug effects; D004311:Double-Blind Method; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D014859:Warfarin / Q000494:pharmacology*
chemical_list: D018712:Analgesics, Non-Narcotic; D000925:Anticoagulants; D000082:Acetaminophen; D014859:Warfarin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase