INTERACTION BETWEEN
PARACETAMOL AND
WARFARIN IN PATIENTS: A
DOUBLE-BLIND, PLACEBO-
CONTROLLED, RANDOMIZED
STUDY
นสภ. มารุตต์ ตรีอน
ิ ทอง
รหัส 47210463
นสภ. ชฎาพร พรมปั ญญา รหัส 47230007
ี งรายประชานุเคราะห์
แหล่งฝึ ก : โรงพยาบาลเชย
OBJECTIVE
Main
assess the effect of paracetamol
on the INR in patients receiving a
stable regimen of warfarin
OBJECTIVE
Secondary
+investigate the mechanism
+evaluate a correlation between INR
variation and paracetamol intake
+determine a min. duration of
paracetamol administration which does not
cause significant INR variations
+identify early variations in clotting
factor activities
PATIENTS
 20
outpatients, both sex, 18+ years
 Target INR 2-3
 On stable warfarin > 1 m (2-9
mg/day)
 No recent or ongoing diseases
 The intake of concomitant Tx as well
as medication known to affect INR
values allowed on condition that
dosages were kept constant
throughout the trial
STUDY DESIGN
Single-center, double-blind,placebocontrolled, randomized and crossover study
20 pts
10: placebo
14 d
10: paracetamol 4 g*
14 d
Wash-out period
14 d
Paracetamol 4 g
14 d
*Doliprane®, 500 mg capsule
Placebo
14 d
STUDY DESIGN (CONT.)
Run-in period
Verify stability anticoagulant treatment
D 0 (before 1st
medication intake)
Physical examine and blood sample
taken at hospital
D 2, 4, 7, 9, 11 and
14
Visit at home
-examine signs of hemorrhage and thrombosis
-ask about possible lapses from the protocol
Ex. changing any OTC or prescription drugs
-counting the returned empty blister packs and
the unused paracetamol and placebo capsules
-evaluate alcohol consumption and dietary
intake of food containing vit.K
 Intra-individual
variability of INR = 0.3
(previous studies) => INR increase > 0.5 was
significant and related to an interaction
between paracetamol and warfarin
 If
2 successive INR values were >3.5, warfarin
was to be discontinued then restarted at the
same dose as before
 If INR remained outside the target range
during the wash-out period , the warfarin
regimen was readjusted and the pt entered the
2nd study period after stabilization on the new
dose
RESULT
 Mean
age: 62±19 years (range 24-89 years)
 19 (10 women and 9 men) completed the study
 1 pt withdrew her consent for personal reason
after 4 days in the 1st period and 1 pt had a
serious protocol deviation => excluded from final
analysis
 No bleeding events
 The paracetamol regimen was stop in 4 pts and
1 pt in placebo administration because of
increases in 2 consecutive INR values
RESULT (CONT.)
1
pt had a serious non-drug-related
adverse event (hospitalization for a
sinoatrial block) and discontinued the
trial on day 4 of the 2nd period
RESULT (CONT.)
 No
significant variations in INR were
observed during the placebo period
 Paracetamol therapy significant rise in
mean INR was observe within 2 day
 Continued to increase until day 7 and
remained significant enhanced until the
end of the Tx period
 In
each pt, the mean INR peak was
significantly higher in the paracetamol
period than in the placebo period
RESULT (CONT.)
 The
mean absolute AUC of factor II,VII and X
chandes from baseline were significantly
greater during the paracetamol period than
during the placebo period
 No significant variation in factor V levels
CONCLUTION
 Mean
INR rose rapidly after the start of
patacetamol and significantly increase
within 1 week of paracetamol intake
 Paracetamol intake were signigicant
reduction in the vitamin K-dependent
clotting factor II, VII, and X
เหตุผลทีไ่ ม่เห็นด้วยก ับ
ข้อมูลด ังกล่าว
ึ ษา
รูปแบบการศก
ึ ษา
 จานวนของผู ้ป่ วยในการศก
 ขนาดยา
 การตรวจติดตาม
้
 การประเมินความร่วมมือการใชยาตามส
งั่
 ความแปลผันของ
INR
เกณฑ์การค ัดเข้า/ค ัดออก
ึ ษา
จากการศก
 ความคงทีข
่ อง
INR
 การรับประทานยาอืน
่ ร่วมด ้วย
ึ ษา
ล ักษณะต่างๆ ของกลุม
่ ศก
่ งอายุ
 ชว
 โรคร่วมอืน
่ ๆ
 ยาอืน
่ ๆทีไ่ ด ้รับ/สมุนไพร
Thank You
& Questions