The oral anticoagulant dilemma

Warfarin, the most commonly used oral anticoagulant in Australia, is highly effective in a wide range of thromboembolic disorders, including prevention of stroke in patients with atrial fibrillation, thrombus formation in patients with prosthetic heart valves and prevention and treatment of venous thromboembolism (VTE).^1, 2 Challenges associated with warfarin therapy have prompted the development of a number of novel oral anticoagulants (NOACs), of which dabigatran, apixaban and rivaroxaban are available in Australia and listed on the Pharmaceutical Benefits Scheme (PBS).^3, 4

This therapeutic brief provides information to help make an informed decision when considering which oral anticoagulant is most appropriate for your patient.

Table 1: Comparison of novel oral anticoagulants and warfarin

	dabigatran (Pradaxa)4, 5, 8	apixaban (Eliquis)4, 6, 8	rivaroxaban (Xarelto)4, 7, 8	warfarin (Coumadin, Marevan)8
Actions	Direct thrombin inhibitor	Direct and selective inhibitor of factor Xa	Direct and selective inhibitor of factor Xa	Inhibits synthesis of vitamin K-dependent clotting factors II, VII, IX, X and antithrombotic factors protein C and S
Indications	Prevention of: VTE in total hip or knee replacement stroke and systemic embolism in non-valvular AF and at least one additional risk factor for stroke	Prevention of: VTE in total hip or knee replacement stroke and systemic embolism in non-valvular AF and at least one additional risk factor for stroke	Prevention of: VTE in total hip or knee replacement stroke and systemic embolism in non-valvular AF and at least one additional risk factor for stroke treatment of DVT/PE and for prevention of recurrent DVT/PE	Prevention of: VTE and treatment for VTE VTE in patients with prosthetic heart valves stroke and systemic embolism in AF
Onset of action / Half-life	Onset of action within 30 minutes. Half‑life is 7-9 hours in young adults and 12-14 hours in elderly people. Half-life is prolonged in renal impairment	Onset of action within 30 minutes. Half-life is approximately 12 hours	Onset of action within 30 minutes. Half-life is approximately 5-9 hours in young adults and 11-13 hours in elderly people	Onset of action within 36-72 hours. Half-life is 20-60 hours
Dosage	Fixed according to clinical indication	Fixed according to clinical indication	Fixed according to clinical indication	Individualised and dose adjusted according to INR result

We need to be careful that marketing promotion and familiarisation programs do not drive a needless trend to switch patients currently taking warfarin to the new agents for perceived ease of use or claims of superior safety or efficacy.⁹ An informed decision and careful patient selection is recommended when considering treatment options as many patients may not benefit from switching to the new agents.

Which of my patients may do better by continuing with warfarin?

While the novel oral anticoagulants offer an alternative to warfarin therapy for selected patients, like all anticoagulants, they are a class of medicines that can potentially cause severe or fatal bleeding.^1, 8 Novel oral anticoagulants were studied for a median of 19-22 months in clinical trials and in select patient populations. There is limited experience of their safety and efficacy in people with significant renal or liver impairment, the elderly and those with multiple comorbidities and concurrent medicines. Associated adverse effects, complications and interactions in these patient populations remain largely unknown.^5-7

Hence, careful consideration is advised before switching patients from warfarin to a novel oral anticoagulant as there is risk associated with changing medicines, especially in a population that is predominantly elderly with multiple comorbidities and concurrent medicines.^10-12 There is a familiarity, level of comfort and a wealth of experience associated with the use of warfarin because of its long term use, extensive experience in clinical trials and the ability to reverse its anticoagulant effects, if required.^2, 13 It is likely patients will be asking about the novel oral anticoagulants.

The stable patient

Although the risk of intracranial haemorrhage is less with the novel oral anticoagulants, this alone does not warrant switching your patient from warfarin.^10, 13 Stable patients taking warfarin whose international normalised ratios (INRs) are largely within the targeted therapeutic range and in whom INR testing does not present a problem, may not benefit from switching.¹³ In stable well controlled patients taking warfarin, there is evidence that the benefits of the novel oral anticoagulants, particularly dabigatran, decrease as time in the therapeutic range (TTR) increases.^14, 15 The importance of frequent patient contact that is inherent with regular INR monitoring cannot be over emphasised. As well as measuring anticoagulant response and assessing patient adherence, regular contact offers an opportunity to clinically monitor the patient and reinforce key aspects of treatment.^14, 15

If your patient does not have INR results within the therapeutic range most of the time and you are considering switching to a novel oral anticoagulant, first assess correctable causes for INR variation. (See Box 1).

The non-adherent patient

Patients taking warfarin who have difficulty in maintaining correct dosing regimens should not be switched to a novel oral anticoagulant. Because of the shorter half-life of the novel oral anticoagulants, a missed dose is more likely to cause a significant or complete loss of antithrombotic effect.^13, 14 Likewise, taking additional doses is likely to increase the risk of a bleed.¹¹ Dabigatran and apixaban in particular, should not be considered alternatives to warfarin in poorly adherent patients as they need to be taken twice daily.^5, 6, 13 Because there is no validated laboratory method to measure the anticoagulant response of the novel oral anticoagulants, the first sign of poor compliance may be seen as a stroke or other embolic event or as a bleed.^5-7, 14 Therefore, strict adherence is essential for adequate anticoagulant protection with novel oral anticoagulants.¹⁰

The multimorbid patient

The prevalence of multimorbidity increases with age, with those over 40 years ten times more likely to take four or more prescribed medicines each day, potentially putting them at a high risk of medicine-related adverse effects.¹⁷ The extent and clinical significance of interactions between many medicines and novel oral anti­coagulants are currently unknown. The detection of these interactions may be difficult due to the lack of a validated measure of anticoagulant response. Caution is recommended when starting, stopping or adjusting the dose of any medicine or anything that may increase the bleeding risk.² As with warfarin, there is an increased risk of major bleeding when novel oral anti­coagulants are taken in combination with any anti­platelet therapy, non-steroidal anti-inflammatory drugs (NSAIDs), fish oil, selective serotonin reuptake inhibitors (SSRIs) or other anticoagulants.^{1, 5-7, 18-20} The risk increases significantly with the addition of a single antiplatelet with a novel oral anti­coagulant. This suggests caution when considering combining these medicines with any oral anticoagulant.¹⁸

Contraindications and cautions with novel oral anticoagulants

Contraindications

• All novel oral anticoagulants are contraindicated in patients:
  • with a known hypersensitivity or condition/s associated with a significant increased risk of bleeding^5-7
  • with valvular atrial fibrillation, (including rheumatic valvular disease or a prosthetic heart valve)⁸
  • with significant hepatic disease^5-7
  • undergoing dialysis.^6, 7, 11
• dabigatran is contraindicated in patients with a creatinine clearance less than 30mL/minute.⁵
• rivaroxaban is contraindicated in patients with a creatinine clearance less than 30mL/minute for 15mg and 20mg tablets and in patients with a creatinine clearance less than 15mL/minute for 10mg tablets.⁷
• apixaban is contraindicated in patients with a creatinine clearance less than 25mL/minute.⁶

NOTE: for further details on contra­indications, see Product Information for each novel oral anticoagulant.

Cautions

The renally impaired and elderly patient

• Exercise caution in patients with mild to moderate renal impairment especially if considering the use of dabigatran as it is predominantly excreted via the kidneys.^5, 10, 20
• Careful consideration in the elderly is advised as renal function commonly declines with increasing age and the risk of incurring a major bleed increases in those people 75 years of age and over.^5-8, 20
• Consider a reduced dose if your patient has moderate renal impairment (creatinine clearance 30-50mL/minute), is 75 years or older or has a potentially higher risk of major bleeding.^5-7

The low body weight patient

• Patients with low body weight may be at an increased risk of bleeding.²¹

The patient with a history of GI bleeding

• Bleeding in the lower gastrointestinal tract, gastritis and dyspepsia are all more common in patients receiving dabigatran or rivaroxaban, compared with warfarin, especially in people over the age of 75 years.^5, 7, 20
• Older people who have a history of lower gastrointestinal disease or bleeding may be at an increased risk of harm with the use of dabigatran or rivaroxaban.¹⁴

The patient with mild to moderate hepatic disease

• Caution is advised in patients taking apixaban with mild to moderate hepatic dysfunction.⁶
• Use rivaroxaban with caution in cirrhotic patients with moderate hepatic dysfunction.⁷

No reversal agent

• It is difficult to manage bleeding associated with the novel oral anticoagulants. As there is no specific pharmacological antidote currently available for any of the new agents, their actions are not able to be effectively and rapidly reversed. Thus management is largely supportive.^5-7, 14
• This is particularly hazardous in patients experiencing an overdose, major bleeding such as intracranial/extracranial or gastrointestinal bleeding, and during emergency invasive procedures.^2, 14

Increased risk of myocardial infarction

• There is evidence to link the use of dabigatran with a small increased risk of myocardial infarction or acute coronary syndrome.²²

Which of my patients would I consider switching to a novel oral anticoagulant?

When determining whether your patient currently taking warfarin would benefit from switching to a novel oral anticoagulant, give careful consideration to the clinical profile of the patient, the specific aspects of the new medicine and the risks and benefits and safety issues associated with switching medicines.^11, 13, 14 Discuss treatment options with your patient and ensure they are aware of the advantages and disadvantages, including the importance of regular monitoring, strict adherence and bleeding risks.

Patients currently taking warfarin most likely to benefit from continuing with warfarin	Patients who may benefit from switching to a novel oral anticoagulant23
Well controlled in whom INR testing is not a problem	Poorly controlled
May miss a dose	Unable to access INR testing
Valvular atrial fibrillation or prosthetic heart valve (NOACs are contraindicated)	Unable to tolerate warfarin
Significant renal impairment	Unwilling to take warfarin
Significant hepatic impairment
Over 75 years with multimorbidities
Lower gastrointestinal disease or history of bleeding

Managing patients taking novel oral anticoagulants

If you have made the decision to initiate a novel oral anticoagulant, make sure it is the most appropriate oral anticoagulant for your patient and that any medicines that increase the bleeding risk, such as low molecular weight heparin, antiplatelet therapy, aspirin or NSAIDs have been ceased or their continuation has been carefully considered.^5-7, 18-20

If you have made the decision to switch your patient from warfarin to a novel oral anticoagulant, monitoring of the patient remains crucial. Although routine laboratory monitoring is not suitable for dose adjustment, the importance of regular clinical monitoring of the patient cannot be over emphasized.^10, 23 This is of particular importance during the early stages of treatment as patients may differ from those included in trial populations and adverse effects may be unpredictable.³ Regular clinical review with the patient will enable opportunities to closely reassess for bleeding risk, reinforce key aspects of treatment such as adherence and assess tolerability.¹¹

All novel oral anticoagulants require dose reduction depending on renal function.^10, 11 Assess renal function at initiation of treatment and at least annually thereafter. Assess renal function more often in patients receiving dabigatran or in patients potentially at risk of declining renal function, such as frail or elderly people or where a decline in renal function may be suspected.¹¹ Assess current liver function as a baseline prior to commencing any of the novel oral anticoagulants, especially if there is suspicion of hepatic dysfunction, as it is not recommended to commence patients with significant liver disease on any of the novel oral anticoagulants.^5-7

Educating patients taking oral anticoagulants

Evidence suggests patients who have a poor understanding of their anticoagulant therapy are at an increased risk of bleeding complications and poor anticoagulant control. Educating patients to include fundamental aspects of their treatment such as recognising signs and symptoms of bleeding and when to report them, and the importance of adherence to dosing and regular monitoring may reduce bleeding complications.²⁵ Encourage your patient to carry details of their anticoagulant therapy with them at all times.¹¹

No matter what oral anticoagulant you choose for your patient, the importance of regular monitoring and frequent reviews in managing a potentially complex patient population cannot be over emphasised.

INSERT: Medicines Review for patients prescribed anticoagulants

The therapeutic brief provides detailed information about warfarin and the recent extension of PBS listing for novel oral anticoagulants (NOACs), and highlights important considerations for use of these medicines.

With the recent expanded availability of the novel oral anticoagulants, GPs may be reviewing their patients who are prescribed warfarin. Regardless of anticoagulant type, patient education is vital in maximising the benefits of therapy while minimising the risk of bleeding. For patients prescribed warfarin, having a Home Medicines Review (HMR) can delay the time to next hospitalisation for bleeding.¹

If you do receive such a referral, consider the points below as part as your review process. It is likely that the patient’s GP will value concise feedback that includes any education provided to the patient, and your assessment of whether the patient is stable on current therapy, or is experiencing any difficulty with adherence so may benefit from further support.

If no problems are identified through the review, this is important information that should also be outlined in your feedback to the GP.

HMRs can improve health outcomes for members of the veteran community.² Thank you for your work with veterans, we hope this information helps you respond to a GP’s medicine review referral for patients prescribed an anticoagulant.

1. Roughead EE, Barratt JD, et al. Collaborative home medicines review delays time to next hospitalization for warfarin associated bleeding in Australian war veterans. Journal of Clinical Pharmacy and Therapeutics 2011; 36: 27-32.

2. Roughead EE, Barratt JD, et al. The effectiveness of collaborative medicine reviews in delaying time to next hospitalisation for heart failure patients in the practice setting: results of a cohort study. Circulation: Heart Failure 2009; 2(5): 424-8.

References

1. Therapeutic Guidelines: Cardiovascular. Version 6. 2012. Melbourne: Therapeutical Guidelines Ltd.
2. Australian Department of Health and Ageing. Review of anticoagulation therapies in atrial fibrillation. 2012. Available at: http://www.pbs.gov.au/info/publication/factsheets/shared/anticoagulation-review [Accessed 2 July 2013].
3. Australian Department of Health and Ageing. Issues and Options Paper: Review of Anticoagulation Therapies in Atrial Fibrillation, June 2012. Available at: http://www.pbs.gov.au/reviews/atrial-fibrillation-files/issues-and-options-paper.pdf [Accessed 5 August 2013].
4. NPS MedicineWise. Anticoagulant listings. 2013. Available at: http://www.nps.org.au/health-professionals/resources-and-tools/decision-and-management-tools/decision-tools/anticoagulants-listings [Accessed September 2013].
5. Australian Department of Health and Ageing. Therapeutic Goods Administration. Pradaxa (dabigatran etexilate). Available at: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-01177-3 [Accessed 30 July 2013].
6. Australian Department of Health and Ageing. Therapeutic Goods Administration. Eliquis (apixaban). Available at: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-03072-3 [Accessed 30 July 2013].
7. Australian Department of Health and Ageing. Therapeutic Goods Administration. Xarelto (rivaroxaban). Available at: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-01020-3 [Accessed 30 July 2013].
8. Australian Medicines Handbook, Adelaide: Australian Medicines Handbook Pty Ltd 2013.
9. Attia J. & Pearce R. The use, misuse and abuse of dabigatran. MJA. 2013; 198(7): 356-357.
10. John Camm A. et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation. European Heart Journal. 2012. Available at: http://eurheartj.oxfordjournals.org/content/33/21/2719.full.pdf+html [Accessed 30 July 2013].
11. Heidbuchel H. et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. European Heart Journal. 2013. Available at: http://eurheartj.oxfordjournals.org/content/34/27/2094.full.pdf+html [Accessed 30 July 2013].
12. Gattellari M. et al. Outcomes for patients with ischaemic stroke and atrial fibrillation: the PRISM study (a program of research informing stroke management). Cerebrovascular Diseases. 2011; 32: 370-382.
13. Weitz J. & Gross P. New oral anticoagulants: which one should my patient use? Haematology. 2012; 2012(1): 536-540.
14. Schulman S. & Crowther M. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood. 2012; 119(13): 3016-3023.
15. Adam S. et al. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Annals of Internal Medicine. 2012; 157: 796-807.
16. NPS MedicineWise Professional. Anticoagulants safety. 2013. Available from: http://www.nps.org.au/medicines/heart-blood-and-blood-vessels/anti-clotting-medicines/for-individuals/anticoagulant-medicines/for-health-professionals/decision-tools/anticoagulants-safety-checklist [Accessed 19 August 2013].
17. Taylor A. et al. Multimorbidity – not just an older person’s issue. Results from an Australian biomedical study. BioMed Central Public Health. 2010; 10: 718-728.
18. Dans A. et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial. Circulation. 2013; 127: 634-640.
19. Oldgren J. et al. New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis. European Heart Journal. 2013; 34: 1670-1680.
20. Majeed A. et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. A meta analysis. Available from: http://circ.ahajournals.org/content/early/2013/09/30/CIRCULATIONAHA.113.002332 [Accessed 7 October 2013].
21. Harper P., Young L. & Merriman E. Bleeding risk with dabigatran in the frail elderly. New England Journal of Medicine. 2012; 366(9): 864-866.
22. Uchino K. & Hernandez A. Dabigatran associated with a higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med. 2012; 172(5): 397-402.
23. NPS MedicineWise. Good anticoagulant practice. 2013. Available at: http://www.nps.org.au/__data/assets/pdf_file/0020/222077/MedicinewisNewsFEB2013-anticoagulants-with-note.pdf [Accessed 19 August 2013].
24. Boehringer Ingelheim Pty Ltd. Pradaxa Capsules. Consumer Medicine Information. 2013. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-CMI-01176-3 [Accessed September 2013].
25. Kagansky N. et al. Safety of anticoagulation therapy in well-informed older patients. Arch Intern Med. 2004; 164: 2044-2050.
26. Roughead E. et al. Collaborative home medicines review delays time to next hospitalisation for warfarin associated bleeding in Australian war veterans. Journal of Clinical Pharmacy and Therapeutics. 2011; 36: 27-32.

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