Antiphospholipid Syndrome, Atrial Fibrillation, Deep Venous Thrombosis, Pulmonary Embolism, Stroke
Conditions
Keywords
paracetamol, warfarin, drug interaction, pathogenic mechanism
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.
Interventions
DRUGparacetamol
Treatment consisted of two paracetamol 500mg (Doliprane® 500mg, Sanofi-aventis, Paris, France) tablets twice a day along with two matching placebo tablets once daily
DRUGPlacebo
Treatment consisted of two matching placebo tablets three times a day.
Sponsors
Hopital Lariboisière
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SCREENING
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The mean maximum increase in INR from baseline to Day 10 (INR (max-D1)) | 10 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The time to the first variation of INR observed | 10 days | — |
| Day 10 - Day 1 differences in factors II, V, VII, AT-III plasma concentrations between groups. | 10 days | — |
| Day 10 - Day 1 differences in paracetamol plasma concentration between groups. | 10 days | — |
| The mean maximum INR (INRmax) | 10 days | — |
| Day 10 - Day 1 differences in Gla-type Osteocalcin (Gla-OC) and undercarboxylated Osteocalcin (Glu-OC)plasma concentrations between groups. | 10 days | — |
| Relation between age and the mean maximum increase in INR from baseline to Day 10 (INR (max-D1) | 10 days | Relation between age and INR (max-D1)is measured using regression analysis. |
| Day 10 - Day 1 differences in R(-), S(-)warfarin plasma concentrations between groups. | 10 days | — |
Countries
France
Outcome results
None listed