This site is intended for health professionals only

Oral anticoagulation management in primary care

There are an estimated 1.25 million people taking long-term oral anticoagulants in the UK.1 This number is on the increase as a consequence of warfarin prescribing for stroke prevention in patients with atrial fibrillation (AF). It is also used to prevent thromboses primarily in patients with venous thromboembolism (VTE) and heart valve replacements.

The National Institute for Health and Care Excellence (NICE) guidelines for AF2 recommend warfarin therapy for stroke prevention in people with AF and other risk factors. The latest European Society of Cardiology (ESC) guidelines3 recommend and define those risks in more detail with cardiac failure, hypertension, age, diabetes, and stroke (CHADS2) scores and and CHADS-vascular disease, age and sex (VASc) scores to assist in determining which patients require anticoagulation.

Until recently most patients on oral anticoagulation therapy in the UK received warfarin - a vitamin K antagonist that interferes with the action of factors II, VII, IX and X as well as the natural anticoagulant proteins C and S. However, there are now alternative novel anticoagulants which target other parts of the coagulation pathway, factor Xa and thrombin factor II inhibitors. Some of these drugs are now approved by NICE6,7 for use in adult patients for stroke prevention with atrial tibrillation and also for venous thromboembolism prevention and treatment. The indications and care pathways in primary care for warfarin and the novel anticoagulants in relation to AF and VTE treatment are outlined below.

Warfarin indications and management 

Warfarin has a narrow therapeutic window and the required intensity of action varies depending on the clinical indication. Expert guidelines recommending target international normalised ratio (INR) for the various conditions requiring warfarin therapy have been produced by the British Committee for Standards in Haematology (BCSH)4 which were  updated in 2011.5

As it is vital when prescribing warfarin to balance between the beneficial effects of preventing thromboembolism and the hazardous effects of excessive thinning of the blood, treatment requires careful monitoring and dose adjustment.

The dose of warfarin is affected by age, coexisting diseases, diet, alcohol consumption, interacting drugs and adherence to 

the drug. 

Warfarin management involves four processes:

1. Measurement of INR.

2. Interpretation of the INR result (whether it is within the target range set for the clinical condition).

3. Advice on the warfarin dosage (whether to increase or decrease the anticoagulant therapy). 

4. Management of complications of therapy (bleeding or thrombotic events). 

For the first process, INR testing, point-of-care devices (POC) are predominantly used in primary care. POC tests are diagnostic tests undertaken outside the laboratory setting,5 and technological advances have made them suitable for use by non-laboratory personnel, including patients. 

For the second process, interpretation of the INR result and management of the result, the National Patient Safety Agency (NPSA)6 recommend the use of computerised decision support software (CDSS) to determine the dose and recall for individual patients. They also have an important function in auditing the anticoagulant service. There are a number of systems available, some of which are particularly appropriate for primary care use. 

The key messages for management of warfarin within primary care are the following:

  • To ensure the necessary healthcare professionals have the required competencies as laid out by the NPSA.
  • To ensure an INR result is seen and the patient is being monitored regularly before prescribing warfarin to a patient.
  • To make arrangements for additional INR monitoring before co-prescribing a medicine that may interact with warfarin. 
  • To review and update clinical protocols relating to the anticoagulant pathway regularly. 
  • To ensure all dose changes for patients in nursing homes are confirmed in writing 
  • To ensure all patients on anticoagulation therapy have received appropriate verbal and written information at the start and throughout treatment.
  • To ensure annual audit of a wide range of safety indicators to ensure a high quality service.

Novel oral anticoagulants 

There are currently three new agents licensed for stroke prevention in atrial fibrillation and one agent licensed for treatment and secondary prevention of venous thromboembolism.

The three agents currently available are: dabigatran etexilate, a direct thrombin inhibitor; rivaroxaban, and apixaban, both factor Xa inhibitors.

All three of these new agents are licensed in the UK for adult patients with non-valvular atrial fibrillation with at least one additional risk factor, broadly defined as:

Previous stroke, transient ischaemic attack, or systemic embolism.

Heart failure.

Age 75 or older.

Age 65 or over with diabetes, coronary heart disease or hypertension.

There are subtle differences to the specific indications however essentially they match the conditions for patients who would previously have been considered suitable for warfarin.

The evidence for utilisation of these agents for stroke prevention for atrial fibrillation is based on large randomised trials.  

There are currently NICE technology appraisals available for dabigatran,6 and rivaroxaban7 which provide further details. The technology appraisal for apixaban is due to be published in 2013. It is clear however from the technology appraisals that these new agents should be made available for patients who require them, but that the decision on choice of agent should be undertaken only following an informed discussion with the individual patient.

In addition, rivaroxaban is licensed for the treatment and secondary prevention of venous thromboembolism.

Dabigatran is an oral agent with fixed dosing which requires no anticoagulation monitoring. Its efficacy and safety were demonstrated in the RE-LY trial,8 a multi centre study which compared two doses of dabigatran with adjusted dose warfarin, aiming for an INR of between two and three. The results demonstrated superiority of higher dose dabigatran (150 mg bd) in terms of the primary end-point, with similar safety data in terms of bleeding, while the lower dose of dabigatran (110 mg bd) demonstrated similar efficacy in terms of the primary outcome with a superior safety profile in terms of bleeding data. Interestingly both doses of dabigatran resulted in lower rates of intra-cranial haemorrhage.

Rivoaroxaban is an oral agent with fixed dosing that requires no anticoagulation monitoring. Its safety and efficacy were demonstrated in the ROCKET-AF trial,8 a double blind study which compared fixed dose rivaroxaban (20 mg once daily) to adjusted dose warfarin (INR two to three). There was no statistical difference in stroke, major bleeding or mortality between the two arms, although there was a lower rate of intra-cranial bleeding in the rivaroxaban group.

Apixaban is an oral agent with fixed dosing which requires no anticoagulation monitoring. Its safety and efficacy were demonstrated in the ARISTOTLE trial,9 a double-blind trial which compared fixed dose apixaban (5 mg once aily) to adjusted dose warfarin (INR two to three). Apixaban was superior to warfarin in terms of stroke reduction, had similar outcome in terms of major bleeding, and showed a small but statistically significant reduction in overall mortality compared to warfarin (3.5 vs 3.9%, RR 0.89). 

The negative aspects of the new agents are that there are currently no specific reversal agents available in case of emergencies, that whilst no anticoagulation monitoring is required there needs to be something which can be measured in an emergency situation to assess the extent of drug effects, and cost is likely to be prohibitive, at least initially.

Although no anticoagulation monitoring is required for any of these agents, it is important to keep a check on renal function, with none of these agents recommended for use in severe renal impairment (creatinine clearance

It must also be kept in mind that these agents remain potent anticoagulants, and as such the same caution regarding their use needs to be applied as it would to the traditional anticoagulants.

Although no routine anticoagulation monitoring is required, it would seem sensible to review these patients at some point. Adherence is obviously an issue, care needs to be taken with concomitant medication, and renal function will need to be checked intermittently. Local protocols regarding follow-up arrangements are emerging and it would be sensible for primary care clinicians to liaise with local services with regards to these policies.

Suggested care pathway for new oral anticoagulants (NOACs)

  • Produce a computer list of patients with AF and check CHADS2, CHADS-VASc score.
  • Check for patients with a CHADS 2 score of greater than two currently undertreated on aspirin or nothing.

 

Patient assessment, education and choice

  • Discuss which anticoagulant is appropriate for the patient.
  • Consider a trial of warfarin.
  • Consider renal function/liver function/anaemia.
  • Consider interacting drugs.

 

Baseline visit

1. Blood tests to include renal function - EGFR, INR, PT, APPT.

2. Review concomitant medicine interaction, eg verapamil, ketoconazole, cyclosporine, amiodarone, quinidine, rifampicin, St Johns Wort, phenytoin, non-steroidal anti-inflammatory drugs (NSAIDs).

3. Education - discuss pros and cons of warfarin versus new anticoagulants.

4. Discuss adherence, dosing, monitoring, adverse events.

6. Switch from warfarin if INR is 2.0 or below.

7. Start medication.

8. Documentation (some CDSS systems have a resource for this).

 

Conclusion

Essentially we now have three novel anticoagulants in addition to warfarin available which are suitable for use in patients with atrial fibrillation at risk of stroke. They are all good in terms of efficacy and safety which makes it difficult to distinguish between them. 

Concerns remain over the long-term safety of the newer agents and their use in routine practice. The newer agents are potent anticoagulation therapy and it is imperative that both patients and healthcare professionals treat them as such. While the new agents provide the possibility of a more tailored approach to individual treatment regimes, this brings with it the responsibility of understanding their mechanisms of action and where they will bring benefit over existing agents. 

Managing anticoagulation, both warfarin and the novel anticoagulants, requires a team approach to decide practice protocol components, process for delivery and timeframe. However, the provision of such services in primary care has been shown to make a substantial difference to patients' lives. A well-planned and competently delivered service can be good for both patients and the practice.

 

References

1. Mediplus. Analysis of oral anticoagulant therapy (OAT). London: 

IMS Health; 1999. (Study number MP990207).

2. National Institute for Health and Care Excellence. Atrial fibrillation: 

The management of atrial fibrillation. CG36. 2006. Available at: 

www.nice.org.uk/nicemedia/pdf/CG036niceguideline.pdf

3. ESC guidelines for the management of Atrial Fibrillation ESC guidelines update taskforce. European Heart Journal 2010;31:

2369-429.

4. Baglin T, Keeling D, Watson H. Guidelines on oral anticoagulation (warfarin): third edition - 2005 update. BJ Haem 2005;132:277-85.

5. Keeling D et al, Guidelines on oral anticoagulation with warfarin - fourth edition. BJ Haem 2011;154(3):311-24.

6. National Institute for Health and Care Excellence. Atrial fibrillation - dabigatran etexilate technology appraisal. 2012. Available at: 

www.nice.uk/ta249 

7. National Institute for Health and Care Excellence. Atrial fibrillation (stroke prevention) - rivaroxaban technology appraisal. 2012. 

Available at: www.nice.uk/ta256

8. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. NEJM 2009;361:1139-51. 

9. Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M et al. Apixaban versus warfarin in patients with atrial fibrillation. NEJM 2011; 365:981-992.