1. Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial นศภ. ณัฐวุฒิ ดวงแดง มหาวิทยาลัยเชียงใหม่ นสภ. จตุพร ใจเคลื่อนมหาวิทยาลัย พะเยา นสภ. อังสนา เพ็ญสมบูรณ์ มหาวิทยาลัยพะเยา

2. Click to add Title 1 2 3 4 Title

3. impact factor = 2.743

4. Abstract

5. Introduct ion  The 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

6.  Acetaminophen given at 2 g/day and 3 g/day might potentiate the anticoagulant effect of warfarin Research questions

7. Objec tive  To evaluate the effect of acetaminophen, given at 2 g/day and 3 g/day, on INR in stable patients treated with warfarin

8. Study Design  randomized, parallel (three arms), double- blind, placebo-controlled study

9. 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 remained within normal limits

10. Exclusion criteria  Any treatment change within 7 days before enrollment  Any paracetamol intake within the last 14 days  St John's wort treatment

11. Exclusion criteria  Drug allergy Concomitant drug ( 5- fluorouracile, acetylsalicylic acid, non steroidal anti- inflammatory drugs, chloramphenicol, diflunisal, miconazole)  Pregnancy

12. Drop out  INR value were higher than 3.5  Drug known to interact with warfarin or acetaminophen

13. Method 45 Patients Control group (9)Experimental group (36) 2 g/day (18) 3 g/day (18) Placebo (9) Acetaminophen

14. Method Placebo two placebo tablets three times a day two placebo tablets three times a day 2 g/day two 500 mg tablets twice a day + two placebo tablets once daily two 500 mg tablets twice a day + two placebo tablets once daily 3 g/day two 500 mg tablets three times a day two 500 mg tablets three times a day

15. 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

16. 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

17. Statistics Sample 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% และ β level of 10% -No drop out

18. Statistics ความเหมาะสมของสถิติที่ใช้กับชนิดของตัวแปร - 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

19. Result

20. Fig. 1 Correlation between INR changes and acetaminophen plasma concentrations

21. Result Fig. 2 Correlation between INR changes and factors II plasma concentrations

22. Result Fig. 3 Correlation between INR changes and factors VII plasma concentrations

23.  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

24. 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

25. Generaliza bility - European pt. -> Genetics variation - Life style and environment - Other drugs and agents - Disease

26. Thank you