Anticoagulation: paracetamol caused supratherapeutic INR levels in patients on warfarin.

Clinical bottom line (level 3b)

  1. Patients on warfarin who took more than 2.5 g of paracetamol in the previous week, were at increased risk of having INR >6.0 (NNH = 9 at unknown) . The risk increased as more tablets are taken: 4.5-9.0 g (NNH = 4 at unknown) , 9.0 or more (NNH = 3 at unknown) .
  2. Patients were also at increased risk of supratherapeutic INR:
    • with advanced cancer (NNH = 2 at unknown)
    • who had recently started warfarin potentiating medication (NNH = 4 at unknown)
    • who took more warfarin than prescribed (NNH = 4 at unknown)
    • who had decreased oral intake in the last week (NNH = 8 at unknown)
    • who had an acute diarrhoeal illness in the last week (NNH = 9 at unknown)
  3. Patients appeared to be protected who:
    • had a high vitamin K intake (NNT = 62 at unknown)
    • had 1/2 to 2 alcoholic drinks a day (NNT = 23 at unknown)
Hylek et al: Journal of the American Medical Association 1998; 279 (9): 657-662
Expires June 2003

The study

Case-control study with objective outcomes, adjusted for confounding factors, not validated in an independent set of patients.

Setting: anticoagulation clinic, USA

289 patients (aged mean 70 years, 50% male) outpatient on warfarin for more than one month with a target INR of 2.0-3.0

Excluded if
  • did not speak English
  • admitted to hospital
  • could not be reached by telephone within the designated 24 hour time period


    • Cases: 93 patients (50% male, mean age 70): INR >6.0 (repeated once) (mean INR 8.3)
    Controls: 196 patients (50% male, mean age 70): randomly selected from the clinic with INR 1.7-3.3 (mean INR 2.4)

    Factors studied:
  • INR >6.0


    • Factors summarised:
  • advanced malignancy
  • newly-started potentiating medication
  • warfarin dose more than prescribed
  • decreased oral intake
  • acute diarrhoeal illness
  • high vitamin K intake based on 12 point grading scale for foods rich in it
  • 1-2 alcoholic drinks per week
  • alcoholic drink every other day to 2 per day
  • more than 2 drinks or bingeing
  • 325-2267 mg/week paracetamol (1 to 7, 500 mg tablets)
  • 2275-4549 mg/week paracetamol (5 to 8 tablets)
  • 4550-9099 mg/week paracetamol (9 to 18 tablets)
  • 9100 or more mg/week paracetamol ( > or = 19 tablets)


    • Logistic regression analysis was performed to adjust for confounding factors.

    Outcomes studied:
  • INR>6.0

    • Patients had unblinded telephone interviews about diet and medication after a routine blood test.

    The evidence

    Patient expected event rate for INR>6.0: 5.6%
    risk factor for
    INR>6.0     		adjusted OR
    (95% CI)    		 NNH
    (95% CI)
    advanced malignancy 16.4
    (2.4 to 111)     		2
    (1 to 15)
    newly-started potentiating medication 8.5
    (2.9 to 24.7)     		4
    (2 to 11)
    warfarin dose more than prescribed 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 3.5
    (1.4 to 8.6)     		9
    (4 to 48)
    high vitamin K intake 0.7
    (0.5 to 0.9)     		-62
    (-190 to -37)
    1-2 alcoholic drinks per week 0.7
    (0.3 to 1.6)     		-62
    (-26 to 33)
    alcoholic drink every other day to 2 per day 0.2
    (0.1 to 0.7)     		-23
    (-62 to -20)
    more than 2 drinks or bingeing 0.9
    (0.2 to 4.2)     		-190
    (-23 to 7)
    325-2267 mg/week paracetamol 1.1
    (0.5 to 2.5)     		190
    (-37 to 14)
    2275-4549 mg/week paracetamol 3.5
    (1.2 to 10)     		9
    (3 to 96)
    4550-9099 mg/week paracetamol 6.9
    (2.2 to 21.9)     		4
    (2 to 17)
    9100 or more mg/week paracetamol 10.0
    (2.6 to 37.9)     		3
    (2 to 13)

    • Paracetamol was taken typically for conditions causing acute pain.

    Citation

    1. Hylek EM, Heiman H, Skates SJ, et al: Acetaminophen and other risk factors for excessive warfarin anticoagulation. Journal of the American Medical Association 1998; 279 (9): 657-662
    Search Terms: hand search
    Contributor: Chris Ball and Clare Wotton, June 2000
    Reviewer:

    Clinical Question.
    Patient on warfarin
    Intervention or Exposure risk factors
    Outcome INR>6.0