Clinical Trial: Drug Interaction Between Paracetamol and Warfarin

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Dose-dependent Drug-drug Interaction Between Paracetamol and Warfarin in Adults Receiving Long-term Oral Anticoagulants: A Randomized Controlled Trial

Brief Summary: The objective of this study is to investigate whether paracetamol, given at therapeutic doses (2g/day and 3 g/day), may potentiate the anticoagulant effect of warfarin.

Detailed Summary:

Paracetamol is recommended as a first-line analgesic and antipyretic therapy in patients receiving short- and long-term oral anticoagulation, especially elderly patient.However,Increased INR was previously observed in patients treated with warfarin and paracetamol given at the maximum recommended dose (4g/day).

To date, the mechanism of this interaction has not been determined.A recent in vitro study suggested that the toxic metabolite N-acetyl-para-benzoquinoneimine (NAPQI) appeared to interfere with vitamin K-dependent γ-carboxylase (VKD-carb) and vitamin K epoxide reductase (VKOR) activites12. The question remaining to be dealt with is whether this in vitro observation can explain the in vivo paracetamol-warfarin interaction. We aim to evaluate the effect of paracetamol at the most widely used doses 2 and 3g/day on INR in stable patients treated with warfarin in a double blind randomized placebo-controlled trial and to identify the mechanism involved in this interaction in vivo.


Sponsor: Hopital Lariboisière

Current Primary Outcome: The mean maximum increase in INR from baseline to Day 10 (INR (max-D1)) [ Time Frame: 10 days ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • The mean maximum INR (INRmax) [ Time Frame: 10 days ]
  • The time to the first variation of INR observed [ Time Frame: 10 days ]
  • Day 10 - Day 1 differences in factors II, V, VII, AT-III plasma concentrations between groups. [ Time Frame: 10 days ]
  • Day 10 - Day 1 differences in paracetamol plasma concentration between groups. [ Time Frame: 10 days ]
  • Day 10 - Day 1 differences in R(-), S(-)warfarin plasma concentrations between groups. [ Time Frame: 10 days ]
  • Day 10 - Day 1 differences in Gla-type Osteocalcin (Gla-OC) and undercarboxylated Osteocalcin (Glu-OC)plasma concentrations between groups. [ Time Frame: 10 days ]
  • Relation between age and the mean maximum increase in INR from baseline to Day 10 (INR (max-D1) [ Time Frame: 10 days ]
    Relation between age and INR (max-D1)is measured using regression analysis.


Original Secondary Outcome: Same as current

Information By: Hopital Lariboisière

Dates:
Date Received: April 12, 2010
Date Started: March 2007
Date Completion:
Last Updated: April 13, 2010
Last Verified: February 2010