Use of INR for monitoring warfarin treatment
Full colour PDF of the pages as they appeared in ‘best tests’.
Printer friendly PDF.
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.
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 (Full screen version)
|Risk of Bleeding||Mechanism
|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
|Fluconazole, miconazole (including gel and vaginal preparations)
||Inhibition of warfarin metabolism|
|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|
|Aspirin, clopidogrel, dipyridamole
||Interference with primary haemostasis – increased bleeding risk without alteration of INR|
||Inhibition of warfarin metabolism|
|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|
|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
|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|
- 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
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.
Computerised decision support is a very useful tool for maintaining therapeutic INR levels in patients receiving anticoagulant treatment. There is evidence that computerised decision support can achieve improved therapeutic control in terms of INR, when compared with human performance.14
best practice Decision Support INR module
A best practice Decision Support module has been developed for managing warfarin treatment, based on data from the Coventry system,17 which has been widely accepted internationally.
This module is available free to General Practices in New Zealand. It enables clinicians to more easily adjust oral anticoagulant doses and schedule follow-up consultations. INR results can be tracked and monitored over time and a dose calendar can be printed for the patient.
A meta-analysis of randomised controlled trials compared computerised decision support methods of determining warfarin dosage with traditional manual methods in 3416 patients.15 The computerised decision support groups did better in terms of percentage of INR tests within target (65% computer group, 59% manual group, NNT 17) and showed a significant reduction in the incidence of bleeding (2% computer group, 4.4% manual group).
A randomised controlled trial compared the INR control (by the percentage of time within-target) of two groups of patients attending an anticoagulation clinic in Italy.16 One group were managed using computerised decision support and the other group were dosed using manual methods by experienced haematologists. The INR control in the computerised decision support group was significantly better (71% of time within range for the computer group, 68% for manual group) and fewer tests were needed to achieve this control.15
One of the advantages of computerised decision support tools is that information can be easily retrieved, providing many opportunities for clinical practice audit, including identifying patients who are on anticoagulant treatment but are not receiving INR monitoring.
The bpacnz clinical audit “Safe and effective anticoagulation with warfarin” has been recently updated and is available to download or order.
- Blann AD, Fitzmaurice DA, Lip GYH. Anticoagulation in hospitals and general practice. BMJ 2003;326:153-6.
- Lane DA, Lip GYP. Maintaining therapeutic anticoagulation: The importance of keeping “within range”. Chest 2007;131;1277-9.
- Hylek EM, Evans-Molina C, Shea C, et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007;115:2689–96.
- NHS Sheffield. Primary Care Trust Anticoagulation Monitoring Service standard operating procedure for the provision of a Level 3, 4 and 5 anticoagulation service. NHS Sheffield; March 2008. Available from: www.sheffield.nhs.uk/professionals/resources/anticoagulationservicespec.pdf (Accessed Nov, 2010).
- Kearon C, Kahn S, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th Ed). Chest 2008;133:454S-545S.
- Salem D, O’Gara P, Madias C, Pauker S. Valvular and structural heart disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th Ed). Chest 2008;133:593S-629S.
- Garcia D, Crowther MA, Ageno W. Practical management of coagulopathy associated with warfarin. BMJ 2010;340:918-20.
- Bpacnz. INR testing. October 2006. Available from: www.bpac.org.nz/resources/campaign/inr/bpac_inr_poem_2006_wv.pdf (Accessed Nov, 2010).
- Campbell P, Roberts G, Eaton V, Gallus A. Managing warfarin therapy in the community. Aust Prescr 2001;24:86-9.
- Schurgers LJ, Shearer M, Hamulyak K, et al. Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose–response relationships in healthy subjects. Blood 2004;104:2682-9.
- Juurlink DN. Drug interactions with warfarin: what clinician need to know. CMAJ 2007;177(4):569-71.
- Jaffer A, Bragg L. Practical tips for warfarin dosing and monitoring. Cleve Clin J Med 2003;70:361-71.
- National Guideline Clearinghouse. Anticoagulation therapy supplement. 2006. Available from:www.guideline.gov/summary/summary.aspx?doc_id=9273 (Accessed Nov, 2010).
- Poller L, Wright D, Rowlands M. Prospective comparative study of computer programs used for management of wargarin. J Clin Pathol 1993;46:299-303.
- Bandolier. Computer decision aids for anticoagulation. Bandolier 2001; 87. Available from: www.medicine.ox.ac.uk/bandolier/band87/b87-6.html (Accessed Nov, 2010).
- Manotti C, Moia M, Palareti G, et al. Effect of computer-aided management on the quality of treatment in anticoagulated patients: a prospective, randomized, multicenter trial of APROAT(Automated PRogram for Oral Anticoagulant Treatment). Haematologica 2001;86(10):1060-70.
- Ryan PJ, Gilbert M, Rose PE. Computer control of anticoagulant dose for therapeutic management. BMJ 1989;299:1207-9.
- Baker RI, Coughlin PB, Gallus AS, et al. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. MJA 2004;181(9):492-7.