Use of INR for monitoring warfarin treatment

International Normalised Ratio (INR) testing is well established as an integral part of warfarin treatment. INR has a critical role in maintaining the warfarin response within a therapeutic range, to provide the benefits of anticoagulation, while avoiding the risks of haemorrhage (Figure 1).

Therapeutic monitoring of warfarin treatment requires two key elements to be undertaken if it is to be successful: the measurement of the INR and an interpretation of the result in order to advise on dosage of warfarin and when the next test should be performed.

INR levels can be difficult to control

Although regular testing of INR levels is essential for all people taking warfarin to maintain control of the INR, in practice, INR levels show considerable intra-patient variability. A study has demonstrated that a group of stable patients, on long-term warfarin treatment achieved the therapeutic range for INR approximately 55% of the time.²

Figure 1: Balancing the risk of anticoagulation treatment (adapted from Blann, 2003)¹

Maintaining good systems is important

It is important that practices develop a standardised management protocol for all patients treated with warfarin, in order to optimise health outcomes, by achieving tighter control.

The plan for anticoagulation therapy should be detailed in the patient’s clinical notes, using a standardised method, to minimise misunderstandings. The method chosen will depend on how clinical records are managed within the practice but there should at least be a standard location within the patient notes for the following information:

• A note that the patient is on warfarin
• Condition for which warfarin has been prescribed
• Target INR range
• Planned duration of treatment
• Brand of warfarin

The information that a patient is on warfarin must be immediately obvious to any clinician who accesses the patient’s clinical record.

INR testing schedule

Regular testing of the INR is essential for all people taking warfarin. The risk of bleeding while on warfarin is greatest in patients who have not previously received warfarin, and in the first three months of treatment.³

Any patient on warfarin should be aware of the risks and early warning signs of bleeding, and they should be followed closely, during the first three months in particular, to ensure that the INR does not exceed 3.0.

After this time period, the frequency of INR testing can be reduced. For most people once the INR is stable, the rate of INR testing can be extended to two weekly and then four to six weekly. In some stable patients the frequency may be extended out to eight weeks.⁴ However, people with higher levels of risk, e.g. comorbidities, may need more frequent testing.

Target INR range and duration of treatment

In most situations the INR target is 2.5 (target range 2.0 – 3.0). This range is appropriate for the prophylaxis or treatment of venous thromboembolism and reduction of the risk of systemic embolism for people with atrial fibrillation and valvular heart disease.⁵ In some situations higher ranges are more appropriate. The target INR may vary depending on individual clinical situations. The target INR for mechanical prosthetic valves is dependent on the type of valve replacement used.⁶

The duration of warfarin therapy for a provoked DVT or PE is 13 weeks. For unprovoked DVT or PE the duration again is 13 weeks, but for individual patients within their clinical context, the indefinite use of warfarin may be appropriate.⁵ For atrial fibrillation, cardiomyopathy and valvular heart disease (selected cases) an indefinite period of warfarin treatment is recommended.⁶

Managing alterations in the INR

Some fluctuations in INR level can be expected, and for minor variations, changes in weekly doses are usually not required. For more significant fluctuations, use of a standard guide is important to reduce the risk of incorrect dosing. The use of dosing calendars for more complicated dosage sequencing may be of benefit.

Changes in warfarin dosage may take several days to affect INR level, therefore it is important that doses are not adjusted more frequently than every four to five days.

Changes in the INR level in a usually stable patient may be due to a number of reasons, including:^7,8

• Major changes in diet or alcohol intake
• Drug interactions (pharmaceutical or complementary)
• Systemic or concurrent illness
• Non-adherence to dosage regimen
• Unknown causes

Diet or alcohol

Patients on warfarin are usually advised to consume a reasonably consistent proportion of vitamin K rich foods such as broccoli, spinach and cabbage. This is probably most relevant in patients who have had markedly reduced food intake because of illness, hospitalisation, travel and fad diets.⁹ A recent study suggests that the role of excessive dietary vitamin K may have been overstated, with the exception of natto (Japanese fermented soybean) which causes a marked and prolonged inhibition of warfarin.¹⁰

Increased consumption of alcohol (particularly binge drinking) can affect warfarin control although moderate, regular alcohol consumption has little effect.

Drug interactions

Many medicines and herbal products can interact with warfarin. An interaction can occur when the interacting agent is started or stopped or when the dose is altered. Whilst most interactions involve a change in the INR, it is important to recognise that some interactions cause an increase in bleeding without alteration of the INR, e.g. NSAIDs, aspirin and SSRIs (Table 1).

Table 1 shows some of the important interactions with warfarin. It is not all-inclusive and practitioners should always check if there is a clinically significant interaction if they are prescribing a medicine for a person taking warfarin. Patients should also be advised not to take any other prescribed medicines, over-the-counter medicines or food supplements/herbal products without consulting their doctor or pharmacist.

For a complete list of interactions and advice on managing interactions such as when to check the INR, refer to appropriate information resources such as a formulary or your PMS system.

Table 1: Some of the main medicines, medicine classes and other agents that can interact with warfarin (adapted from Juurlink, 2007)¹¹

	Risk of Bleeding	Mechanism
Antibiotics
Most antibiotics but especially macrolides, metronidazole, quinolones and cotrimoxazole		Inhibition of vitamin K synthesis by intestinal flora, inhibition of warfarin metabolism or both
Rifampicin*		Induction of hepatic metabolism
Antifungals
Fluconazole, miconazole (including gel and vaginal preparations)		Inhibition of warfarin metabolism
Antidepressants
Serotonergic agents (SSRIs and venlafaxine)		Inhibition with platelet function – increased bleeding risk without alteration of INR. Some, e.g. fluoxetine, paroxetine, can also inhibit warfarin metabolism
Antiplatelet agents
Aspirin, clopidogrel, dipyridamole		Interference with primary haemostasis – increased bleeding risk without alteration of INR
Amiodarone		Inhibition of warfarin metabolism
Anti-inflammatory agents
NSAIDS, Cox-2 inhibitors		Direct mucosal injury, antiplatelet effects may also have a role. Increased bleeding risk without alteration of INR. Inhibition of warfarin metabolism and an increase in INR rarely reported with some NSAIDs
Analgesics
Tramadol		Inhibition of warfarin metabolism
Paracetamol		Direct interference with vitamin K cycle Interaction possible with chronic, regular use of paracetamol, short-term (a few days) unlikely to interact
Alternative remedies/foods
Ginkgo, fenugreek, chamomile, dong quai, cranberry products		Unclear, multiple mechanisms
St John’s wort*		Unclear, possible effects on warfarin metabolism
Foods with high vitamin K content, e.g. leafy greens, broccoli*		Increased vitamin K synthesis antagonises anticoagulant effect of warfarin

*These agents will reduce the bleeding risk but the INR may be become sub-therapeutic and warfarin dose may need to be increased

Notes:

• Interactions do not occur, or are not significant, in everyone. There are many variables including genetic factors.
• This table does not include all possible interactions with warfarin. Please check before prescribing or recommending any medicine, herbal product or food supplement

Systemic or concurrent disease

Many systemic diseases can influence INR results:

• Congestive heart failure – may cause hepatic congestion of blood flow and inhibit warfarin metabolism, this may be particularly troublesome during exacerbations of heart failure.
• Hypothyroidism – decreased catabolism of vitamin K clotting factors may decrease INR values.
• Hyperthyroidism – conversely, hyperthyroidism may increase catabolism of vitamin K clotting factors and increase INR values.
• Liver failure – may cause elevation of INR due to reduced production of clotting factors.
• Other illnesses – other intermittent conditions such as fever, vomiting and diarrhoea may affect the INR; ill patients may also reduce their usual dietary intake.

Non-adherence to dosage regimen

An erratic INR may reflect non-adherence to the medicine regimen, often due to misunderstandings of dosage requirements. A missed dose of warfarin is usually reflected in the INR result two to five days after the missed dose,¹² although a response may be seen within 16 hours.¹³

Unknown causes

In many cases, no explanation may be found for unstable INR values. It may be worthwhile discussing aspects of the dosing regimen. Changes in the INR may also be the result of occult causes, such as undisclosed drug use, lifestyle and medical causes.

Current INR is 5–9

1. Stop warfarin
2. Test INR daily until it has returned to the therapeutic range
3. Restart warfarin with a reduced dose when INR < 5
4. Give vitamin K 1.0 – 2.5 mg, orally if INR fails to reduce, or if there is high risk of serious bleeding (N.B. subcutaneous administration is not effective)

Current INR is > 9, without bleeding

Where there is a low risk of bleeding from other causes

1. Stop warfarin therapy
2. Give vitamin K 2.5 – 5 mg, orally
3. Measure INR in 24 hours
4. Restart warfarin with a reduced dose when INR < 5

Where there is a high risk of bleeding from other causes

1. Stop warfarin
2. Seek specialist advice

Current INR is ≥ 9, with minor bleeding

1. Stop warfarin
2. Consider referral to secondary care if clinically appropriate
3. Give vitamin K 1 – 5 mg, orally
4. Test INR daily until stable
5. Restart warfarin with a reduced dose when INR < 5

Major bleeding occurs

If at any time major bleeding occurs:

1. Stop warfarin
2. Give vitamin K 10 mg, slow IV
3. Refer to secondary care immediately for factor replacement