Drug Interaction Between Paracetamol and Warfarin "INPAWA2"

Completed

Phase 4 Results N/A

Trial Description

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 Description

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.

Conditions

Interventions

  • Placebo Drug
    Intervention Desc: Treatment consisted of two matching placebo tablets three times a day.
    ARM 1: Kind: Experimental
    Label: Placebo
    Description: 9 patients on stable warfarin therapy received a 10-day regimen of placebo
  • Paracetamol Drug
    Intervention Desc: Treatment consisted of two paracetamol 500mg (Doliprane® 500mg, Sanofi-aventis, Paris, France) tablets three times a day
    ARM 1: Kind: Experimental
    Label: Paracetamol 2g/d
    Description: 18 patients on stable warfarin therapy received a 10-day regimen of paracetamol 2g/d
    ARM 2: Kind: Experimental
    Label: Paracetamol 3g/d
    Description: 18 patients on stable warfarin therapy received a 10-day regimen of paracetamol 3g/d

Trial Design

  • Allocation: Randomized
  • Masking: Double Blind (Subject, Caregiver, Investigator)
  • Purpose: Screening
  • Endpoint: Safety Study
  • Intervention: Parallel Assignment

Outcomes

Type Measure Time Frame Safety Issue
Primary The mean maximum increase in INR from baseline to Day 10 (INR (max-D1)) 10 days Yes
Secondary The mean maximum INR (INRmax) 10 days Yes
Secondary The time to the first variation of INR observed 10 days Yes
Secondary Day 10 - Day 1 differences in factors II, V, VII, AT-III plasma concentrations between groups. 10 days Yes
Secondary Day 10 - Day 1 differences in paracetamol plasma concentration between groups. 10 days Yes
Secondary Day 10 - Day 1 differences in R(-), S(-)warfarin plasma concentrations between groups. 10 days Yes
Secondary Day 10 - Day 1 differences in Gla-type Osteocalcin (Gla-OC) and undercarboxylated Osteocalcin (Glu-OC)plasma concentrations between groups. 10 days Yes
Secondary Relation between age and the mean maximum increase in INR from baseline to Day 10 (INR (max-D1) 10 days Yes

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