Anticoagulation: acetaminophen and other risk factors cause supratherapeutic INR levels in patients on warfarin

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ANTICOAGULATION: ACETAMINOPHEN AND OTHER RISK FACTORS CAUSE SUPRATHERAPEUTIC INR LEVELS IN PATIENTS ON WARFARIN.

Clinical Bottom Line: (level 3b)

Patients on warfarin who have taken more than 2.5 g of paracetamol in the previous week are at increased risk of having INR > 6.0 (NNH = 9). The risk increases as more tablets are taken (4.5-9.0 g NNH = 4 and > 9.0 g NNH = 3).

Patients are also at increased risk of supratherapeutic INR

with advanced cancer (NNH = 2)

who have recently started warfarin potentiating medication (NNH = 4)

who take more warfarin than prescribed (NNH = 4)

who had decreased oral intake in the last week (NNH = 8)

who had an acute diarrhoeal illness in the last week (NNH = 9)

Patients appear to be protected who

have a high vitamin K intake (NNT = 62)

have 1/2 to 2 alcoholic drinks a day (NNT = 23)

Hylek EM et al: acetominophen and other risk factors for excessive warfarin anticoagulation: JAMA (1998): 279: 657-662
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The Study: case-contol study with objective outcomes and adjustment for confounding factors.

setting: anticoagulation clinic USA
Out-patients (50% male; mean aged 70) on warfarin for > 1 month with a target INR of 2.0-3.0.
cases: 93 patients with INR > 6.0 (repeated once) (mean INR 8.3)
controls: 196 patients randomly selected from the clinic with INR 1.7-3.3 (mean INR 2.4)
Patients had unblinded telephone interviews about diet and medication after a routine blood test

Exposure: paracetamol intake and other events over the last 7 days
Outcome: INR > 6.0
Univariate and logistic regression analysis performed on data

The evidence:

Risk for INR > 6.0 ~ 111/2000 = ~ 5.6%

risk factor

CER

adjusted OR

(95% CI)

NNH*

(95% CI)

advanced malignancy

16.4

(2.4 to 111)

2

(1 to 15)

newly-started potentiating medication

7

(4%)

8.5

(2.9 to 24.7)

4

(2 to 11)

warfarin dose > prescribed

5

(3%)

8.1

(2.2 to 30)

4

(2 to 17)

decreased oral intake

3.6

(1.3 to 9.7)

8

(3 to 64)

acute diarrhoeal illness

15

(8%)

3.5

(1.4 to 8.6)

9

(4 to 48)

high vitamin K intake

79

(40%)

0.7

(0.5 to 0.9)

NNT = 62*

(37 to 190)

aAlcohol:

1-2 drinks pre week

121

(62%)

0.7

(0.3 to 1.6)

NSs

1/2 -2 drinks a day

0.2

(0.1 to 0.7)

NNT = 23*

(20 to 62)

> 2 drinks a day or bingeing

0.9

(0.2 to 4.2)

NSs

*Number of patients with the risk factor that we need to treat with warfarin to cause one patient to have an INR >6.0

*Number of patients with the risk factor that we need to treat with warfarin to needed to prevent one case of INR > 6.0

paracetamol (mg/week)	500 mg tablet equivalents	CER	adjusted OR CI 95%	NNH CI 95%
0	0	126 (64%)	1.0
325 to 2267	1 to 7	46 (23%)	1.1 (0.5 to 2.5)	ns
2275 to 4549	5 to 8	10 (5%)	3.5 (1.2 to 10.0)	9 (3 to 96)
4550 to 9099	9 to 18	9 (5%)	6.9 (2.2 to 21.9)	4 (2 to 17)
³ 9100	³ 19	5 (3%)	10.0 (2.6 to 37.9)	3 (2 to 13)

Comments:

Paracetamol taken typically for conditions causing acute pain
Vitamin K intake based on 12 point grading scale for foods rich in it.

Citation:
Hylek EM et al: acetominophen and other risk factors for excessive warfarin anticoagulation: JAMA (1998): 279: 657-662

Appraised by: CM Ball [cmball@aol.com] on April 3, 1998

Expires: April 2003

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risk factor	CER	adjusted OR (95% CI)	NNH* (95% CI)
advanced malignancy		16.4 (2.4 to 111)	2 (1 to 15)
newly-started potentiating medication	7 (4%)	8.5 (2.9 to 24.7)	4 (2 to 11)
warfarin dose > prescribed	5 (3%)	8.1 (2.2 to 30)	4 (2 to 17)
decreased oral intake		3.6 (1.3 to 9.7)	8 (3 to 64)
acute diarrhoeal illness	15 (8%)	3.5 (1.4 to 8.6)	9 (4 to 48)
high vitamin K intake	79 (40%)	0.7 (0.5 to 0.9)	NNT = 62* (37 to 190)
aAlcohol:
1-2 drinks pre week	121 (62%)	0.7 (0.3 to 1.6)	NSs
1/2 -2 drinks a day		0.2 (0.1 to 0.7)	NNT = 23* (20 to 62)
> 2 drinks a day or bingeing		0.9 (0.2 to 4.2)	NSs