Dose-dependent Drug-drug Interaction Between Paracetamol and Warfarin in Adults Receiving Long-term Oral Anticoagulants: A Randomized Controlled Trial
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 45
- 试验地点
- 1
- 主要终点
- The mean maximum increase in INR from baseline to Day 10 (INR (max-D1))
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Screening
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Paracetamol 2g/d
18 patients on stable warfarin therapy received a 10-day regimen of paracetamol 2g/d
干预措施: paracetamol (Drug)
Paracetamol 3g/d
18 patients on stable warfarin therapy received a 10-day regimen of paracetamol 3g/d
干预措施: paracetamol (Drug)
Placebo
9 patients on stable warfarin therapy received a 10-day regimen of placebo
干预措施: Placebo (Drug)
结局指标
主要结局
The mean maximum increase in INR from baseline to Day 10 (INR (max-D1))
时间窗: 10 days
次要结局
- The mean maximum INR (INRmax)(10 days)
- 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)
- Day 10 - Day 1 differences in R(-), S(-)warfarin plasma concentrations between groups.(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)