Interaction between acetaminophen and warfarin in adults

receiving long-term oral anticoagulants: a

randomized controlled trial

นศภ.ณั�ฐวุ�ฒิ ดวุงแดง มหาวุทยาลั�ยเชี�ยงใหม�นสภ.จตุ�พร ใจเคลั !อน มหาวุทยาลั�ยพะเยานสภ.อ�งสนา เพ$ญสมบู'รณั(มหาวุทยาลั�ยพะเยา

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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