Interaction between acetaminophen and warfarin in adults
receiving long-term oral anticoagulants: a
randomized controlled trial
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Title
impact factor = 2.743
Abstract
IntroductionThe mean INR increase in
patients receiving acetaminophen at the highest recommended dosage (4 g/day)
No prospective study has yet evaluated the effect of acetaminophen at 3 g/day
Acetaminophen given at 2 g/day and
3 g/day might potentiate the anticoagulant
effect of warfarin
Research questions
Objective
To evaluate the effect of acetaminophen, given at 2 g/day and 3 g/day, on INR in stable patients treated with warfarin
Study Designrandomized, parallel (three arms), double-blind, placebo-controlled study
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 olderLaboratory values remained within normal limits
Exclusion criteriaAny treatment change
within 7 days before enrollment
Any paracetamol intake within the last 14 days
St John's wort treatment
Exclusion criteriaDrug allergy Concomitant
drug ( 5-fluorouracile, acetylsalicylic acid, non steroidal anti-inflammatory drugs, chloramphenicol, diflunisal, miconazole)
Pregnancy
Drop outINR value were higher than 3.5
Drug known to interact with warfarin or acetaminophen
Method45 Patients
Control group (9)Experimental group (36)
2 g/day (18) 3 g/day (18)
Placebo (9) Acetaminophen
Method
Placebo two placebo tablets three times a day
two placebo tablets three times a day
2 g/daytwo 500 mg tablets twice a day+ two placebo tablets once dailytwo 500 mg tablets twice a day
+ two placebo tablets once daily
3 g/daytwo 500 mg tablets three times a day
two 500 mg tablets three times a day
Outcome Primary outcome - The mean maximum increase in INR from
baseline to Day 10 secondary outcome - The mean maximum INR - Day 10 - Day 1 differences in factors II, V, VII, AT-III plasma concentrations between groups
Outcome secondary outcome - Day 10 - Day 1 differences in acetaminophen plasma concentration between groups- Day 10 - Day 1 differences in R(-), S(-)warfarin plasma concentrations between groups- Day 10 - Day 1 differences in Gla-type Osteocalcin and undercarboxylated Osteocalcin plasma concentrations between groups
StatisticsSample size and percent drop out
There are 45 pt. in these study.- intra-individual INR variability is 0.3
- expected INR increase of at least 0.5- bilateral α level of 5% แลัะ β level of 10%-No drop out
Statisticsควุามเหมาะสมของสถิตุท�!ใชี+กั�บูชีนดของตุ�วุแปร
- ANOVA-post-hoc test-All statistical analyses were implemented by using Statview v8.0 (SAS Institute, Cary, NC, USA)- Results were expressed as mean and 95% confidence interval (CI), or as a percentage, as appropriate. A P value of 0.05 or less indicated statistical significance
Result
Result
Fig. 1 Correlation between INR changes and
acetaminophen plasma concentrations
Result
Fig. 2 Correlation between INR changes and factors II
plasma concentrations
Result
Fig. 3 Correlation between INR changes and factors VII
plasma concentrations
The lack of variables follow up after withdrawal of acetaminophen
The unexpected imbalance observed in the randomization of the population regarding age, gender and basal warfarin dose
Limitation of Research
Conclusion
- Acetaminophen, 2 g/day and 3 g/day significantly increased the INR in patients treated with warfarin - Recommend close INR monitoring in patients taking acetaminophen during warfarin therapy
Generalizability
- European pt. -> Genetics variation- Life style and environment- Other drugs and agents- Disease
Thank you