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Things that affect our INR

Study
Results
Comment
Sometimes we spot something, half read it, forget it, vaguely remember something about it, and then one day we need to have the information now. For Bandolier that happened with a paper on factors affecting the stability of INR, and especially the effects of paracetamol [1]. Even a hint of what a paper was about can lead to its swift retrieval with modern electronic methods.

Study


This was a case control study conducted at the Mass Gen in Boston. The study was conducted in patients attending the anticoagulant therapy unit (2000 patients) over a single year who had been on warfarin for at least one month, had a target INR of 2.0 to 3.0, and were able to participate in a telephone interview personally or through their carer.

Participants were identified from a daily log of INR tests. Cases were those with an INR greater than 6.0 reported within 24 hours, whose target INR was 2.0 to 3.0; results were verified with a duplicate test. Controls were randomly selected from patients whose target was 2.0 to 3.0 and who had actual values of 1.7 to 3.3.

Some selected cases and controls were ineligible because they did not speak English or because they did not have a telephone, and a few declined to participate. For the others two trained interviewers conducted a scripted interview lasting 10-15 minutes asking about the four weeks before the test. It asked about medicines, newly prescribed medicines, over the counter medicines, dietary habits, alcohol consumption, and prescribed and consumed warfarin doses. Dietary questions specifically asked about gross changes in eating habits, and specifically about 12 foods with high vitamin K content (avocado, broccoli, sprouts, cabbage, peas, lettuce, liver, spinach etc).

Results


There were 93 patients with an INR of more than 6.0 (range 6.1 to 30). For most of them the raised INR represented a recent deterioration in control of their anticoagulation. The mean INR for the test before the four week study period was 2.5 for these same patients, mostly in the range 1.7 to 3.3. Cases and controls were similar in age (mean 70 years), sex (50% women), race (97% white), length of warfarin therapy, and reason for anticoagulation. For half it was atrial fibrillation.

Independent risk factors for an increased risk of INR above 6.0 were (Table 1):



Table 1: Independent risk factors for INR above 6.0

Risk factor Odds ratio 95% CI
For increased chance of INR >6  
Advanced malignancy 16.4 (2.4 to 111)
Newly started potentiating medicine 8.5 (2.9 to 25)
Warfarin dose more than prescribed 8.1 (2.2 to 30)
Eating less vitamin K rich food 3.6 (1.3 to 9.7)
Acute diarrhoeal illness 3.5 (1.4 to 8.6)
   
For decreased chance of INR >6  
Eating vitamin K rich foods 0.7 (0.3 to 0.9)
Alcohol (half to two drinks a day) 0.2 (0.1 to 0.7)
   

Eating more foods rich in vitamin K and a moderate alcohol intake of between one drink every other day to two drinks a day were associated with a lower chance of increased INR.

Paracetamol was also associated with increased risk of elevated INR. Taken mainly for acute pains, the more of it used in the week before the test, the greater the chance of a raised INR (Figure 1). More than nine 500 mg tablets a week gave an odds ratio of 7, and more than 18 tablets a week an odds ratio of 10.

Figure 1: Effect of paracetamol dose on risk of INR above 6.0



Comment


When the INR is above 6 there is an increased risk of major haemorrhage. Maintaining INR values in target ranges in primary care is not always straightforward. There are many hundreds of thousands of people on warfarin, and an average primary care group of 100,000 people may have 1,500 patients on warfarin, predominantly older people with other disorders who take other drugs. The possibilities for drug interactions, and interactions with other features of their lives, is substantial.

The strength of this study from Boston is that it recruited all eligible patients over a year from a busy clinic. It tried to find answers to questions often asked by patients and professionals about whether or how behaviour interferes with INR. Foods, alcohol, over the counter medicines feature in the most commonly asked questions. Answers vary widely - no alcohol, moderate alcohol, doesn't make any difference. Popular textbooks warn about aspirin as analgesics, and often NSAIDs, and can and do suggest paracetamol as a safe alternative.

The truth is different. Eating sensibly, drinking sensibly, taking the right dose of warfarin as prescribed, and avoiding more than five 500 mg (seven 325 mg) tablets of paracetamol a week all help avoid excessively raised INR and give good control. Those dealing with warfarin in primary care could do worse than read this paper and the accompanying editorial [2].

One reason for reading both in some detail is to convince oneself that the interaction with paracetamol is genuine, because the repercussions are major. The background literature describing other types of studies from the dim past in which paracetamol has been shown to interfere with warfarin metabolism and increase the prothrombin time will probably convince.

Analgesia for those on warfarin becomes more difficult if paracetamol is not to be used, nor aspirin, nor NSAIDs. Other nonopioid analgesics that do not interfere with liver metabolism of warfarin are not easy to come by.

References:

  1. EM Hylek et al. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA 1998 279: 657-662.
  2. WR Bell. Acetaminophen and warfarin. Undesirable synergy. JAMA 1998 279: 702-703.
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