Clinical trial NCT01104337: Drug Interaction Between Paracetamol and Warfarin
Official title: Dose-dependent Drug-drug Interaction Between Paracetamol and Warfarin in Adults Receiving Long-term Oral Anticoagulants: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Deep Venous Thrombosis
Pulmonary Embolism
Atrial Fibrillation
Stroke
Antiphospholipid Syndrome
Keywords: paracetamol
warfarin
drug interaction
pathogenic mechanism
Lead sponsor: Hopital Lariboisière
Sponsor class: OTHER
First posted: 2010-04-15
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SCREENING

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 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.

Eligibility criteria: Inclusion Criteria:

* Patients treated with warfarin (target INR 2 to 3) stable anticoagulation at 2 to 9 mg for more than 30 days
* Aged 18 years or older
* Laboratory values (hemoglobin, blood cell counts, albumin, blood ionogram, complementary hemostasis parameters and aspartate, alanine transaminases (AST and ALT))remained within normal limits

Exclusion Criteria:

* Any treatment change within 7 days before enrollment
* Any paracetamol intake within the last 14 days
* Drug allergy Concomitant drug ( 5-fluorouracile, acetylsalicylic acid, non steroidal anti-inflammatory drugs, chloramphenicol, diflunisal, miconazole)
* St John's wort treatment
* Pregnancy

Primary outcomes:
measure: The mean maximum increase in INR from baseline to Day 10 (INR (max-D1))
timeFrame: 10 days
Secondary outcomes:
measure: The mean maximum INR (INRmax)
timeFrame: 10 days
measure: The time to the first variation of INR observed
timeFrame: 10 days
measure: Day 10 - Day 1 differences in factors II, V, VII, AT-III plasma concentrations between groups.
timeFrame: 10 days
measure: Day 10 - Day 1 differences in paracetamol plasma concentration between groups.
timeFrame: 10 days
measure: Day 10 - Day 1 differences in R(-), S(-)warfarin plasma concentrations between groups.
timeFrame: 10 days
measure: Day 10 - Day 1 differences in Gla-type Osteocalcin (Gla-OC) and undercarboxylated Osteocalcin (Glu-OC)plasma concentrations between groups.
timeFrame: 10 days
measure: Relation between age and the mean maximum increase in INR from baseline to Day 10 (INR (max-D1)
timeFrame: 10 days
Other outcomes:
Locations:
city: Paris
country: France
facility: Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboière
Study officials:
affiliation: Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboisière, Paris, France
name: Stephane Mouly, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboisière, Paris, France
name: Guy Simoneau, MD
role: PRINCIPAL_INVESTIGATOR
References: