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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SCREENING
Masking
TRIPLE
Enrollment
45
Treatment consisted of two paracetamol 500mg (Doliprane® 500mg, Sanofi-aventis, Paris, France) tablets twice a day along with two matching placebo tablets once daily
Treatment consisted of two paracetamol 500mg (Doliprane® 500mg, Sanofi-aventis, Paris, France) tablets three times a day
Treatment consisted of two matching placebo tablets three times a day.
Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboière
Paris, France
The mean maximum increase in INR from baseline to Day 10 (INR (max-D1))
Time frame: 10 days
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)
Relation between age and INR (max-D1)is measured using regression analysis.
Time frame: 10 days
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