Conditions that effect our INR
- Laboratory Advice
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 . Even a hint of
what a paper was about can lead to its swift retrieval with modern electronic
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).
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):
- advanced malignancy,
- newly started medicines with the potential to interfere with warfarin
- taking more warfarin than was prescribed
- a decreased consumption of foods rich in vitamin K
- acute diarrheal illness
Table 1: Independent risk factors for INR above
||Odds ratio 95% CI|
|For increased chance of INR
||16.4 (2.4 to 111)|
|Newly started potentiating
||8.5 (2.9 to 25)|
|Warfarin dose more than
||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
|Eating vitamin K rich foods
||0.7 (0.3 to 0.9)|
|Alcohol (half to two drinks a
||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
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
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 .
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.
I have been prescribed Warfarin (3 to 4 mg daily) and am having an INR test
The Warfarin is prescribed as I have Anti-phospholipid Syndrome,
prothrombin 20210A mutation and a protein C deficiency. All three make me a
high risk for thrombosis and heart attack and are complicated by a recent
My question is regarding the INR test (which I beleive is only a calculation applied to
a PT test, should I be concerned that the test uses phospholipid fats in the laboratory PT test, and are the dose rates as advised by my
doctor open to question.
It was difficult for me to interpret your question, but I think you may be
confused about the tests recently performed to evaluate your condition. The
"INR test" is a more reliable way of expressing a PT test result. The INR is
not simply a calculation based on the PT but a way of expressing a PT result
that makes the result easier to interpret, easier to compare to other INR tests
performed in different laboratories and better to appropriately prescribe
Warfarin doses. The PT test does use phospholipids in the testing reagents in
order to perform the test. However, ALL PT tests must use these
phospholipids in order to perform the test. The test could not be performed
without the phospholipids.
I am not able to comment on the decisions made by your doctor. However, the
dose of Warfarin is based on several factors to include body size, PT results,
exercise levels, dietary patterns and the disease being treated. Generally
speaking, a physician is attempting to anticoagulant the patient to reach an INR
of between 2-3. In conditions like stroke and MI, an INR of 2.5-3.5 is
desired. A Warfarin dose of 3-4 mg daily is within an expected dose range.
- EM Hylek et al. Acetaminophen and other risk factors for excessive warfarin
anticoagulation. JAMA 1998 279: 657-662.
- WR Bell. Acetaminophen and warfarin. Undesirable synergy. JAMA 1998 279:
- Tim Randolph, M.S., MT(ASCP)
Assistant Professor of Clinical Laboratory Science Member, ASCLS Consumer Website Response Team September