Good anticoagulant practice

• Stroke risk in people with non-valvular atrial fibrillation (AF) is under-treated even when CHADS2 scores indicate that anticoagulation is required.
  
• People with non-valvular AF well controlled on warfarin may not benefit clinically from switching to a newer oral anticoagulant.
  
• At present, there are no readily available and validated methods for monitoring or reversing the activity of the newer oral anticoagulants.
  
• Coagulation monitoring of patients taking newer oral anticoagulants is not currently possible but routine clinical monitoring is essential.
  

The availability of newer oral anticoagulants, dabigatran, rivaroxaban and apixaban, is an opportunity to review and individualise treatment and prevention of thromboembolism and to improve current warfarin management.

• Start anticoagulants based on a systematic assessment of a person’s potential risk of thromboembolism using the CHADS₂ score (Tables 1 and 2).
  
• Identify risk factors for bleeding as well as patients who need increased clinical monitoring (those with three or more risk factors) using the HAS-BLED tool (Table 3).
  
• People at high risk of bleeding are not precluded from anticoagulation but regular clinical review is recommended.¹
  
• Treat correctable risk factors for bleeding, and consider a Home Medicines Review² for people prescribed anticoagulant therapy. Twice-yearly reviews may benefit patients with three or more risk factors for bleeding.³
  
• Choose an anticoagulant in consultation with the patient; discuss the potential benefits and harms of treatment options.
  
• Consider warfarin as first-line anticoagulant treatment for non-valvular AF.⁴ Aspirin is no longer recommended for people with non-valvular AF who are at moderate risk of stroke unless anticoagulation is contraindicated.⁴
  

^a Per 100 patient-years without treatment.

Assess people with non-valvular AF, who are not already taking anticoagulants, for risk of stroke at least annually, using a tool such as the CHADS₂ scoring system.⁶ 

People with non-valvular AF and one additional risk factor for stroke are considered to be at moderate risk, and people with non-valvular AF and two risk factors are considered to be at high risk of stroke.⁴ Therapeutic Guidelines recommends anticoagulation for these people (CHADS₂ ≥ 1).⁴ 

When the CHADS₂ score is zero, consider using the CHA₂DS₂-VASc score (Table 4) to determine stroke risk and the need for anticoagulation more precisely. Some international guidelines recommend anticoagulation for people with non-valvular AF and a CHA₂DS₂-VASc score ≥ 1 for males and ≥ 2 for females.¹

A recent cohort study of over 132,000 people with non-valvular AF showed that for people with a CHADS₂ score ≥ 1 the benefits of warfarin anticoagulation for reducing risk of stroke outweighed the increased risk of intracranial haemorrhage (ICH) regardless of HAS-BLED score and that warfarin was of no benefit for people truly at low risk of stroke (CHA₂DS₂-VASc score = 0).⁸ 

A meta-analysis showed that aspirin does not significantly reduce incidence of stroke in people with non-valvular AF compared with placebo or no treatment.⁹ In this study, warfarin reduced the incidence of stroke in people with non-valvular AF by 37% compared with antiplatelet therapy (95% confidence interval (CI) 23% to 48%) and is associated with only a small increase in absolute risk of ICH; 0.2% per year.⁹

A 2008 survey of around 600 Australian GPs reported that around 30% are often unsure whether to prescribe warfarin and 38% found it hard to decide if the benefits of warfarin outweigh the risks.¹⁰ 

The decision to prescribe warfarin is influenced both by true contraindications and by factors for which the benefits of anticoagulation outweigh the bleeding risk.¹⁰

Risk of falls

Having a risk of falls is not a direct contraindication to anticoagulant therapy although great care should be taken when treating such people.⁶ 

High risk of falls increases the risk of ICH (hazard ratio [HR] 1.9, 95% CI 1.3 to 2.9)¹¹ and has a significant influence on whether anticoagulants are prescribed.^10,12-15 

A recent cohort study showed that for people with AF, risk of stroke is significantly higher in people at high risk of falls^b than in others (stroke rate per 100 patient–years 13.7 [95% CI 11.6 to 16.3] vs 6.9 [95% CI 6.5 to 7.3], respectively).¹¹ 

In this study warfarin demonstrated significant benefit for people at high risk of falls and high risk of stroke (CHADS₂ score ≥ 2) despite the increased risk of ICH.¹¹ However, warfarin should not be prescribed for people after ICH and risk of falls should be reduced when possible.¹¹

Age

People aged over 70 years are less likely to be prescribed warfarin than people aged under 70 years.¹³ 

A recent meta-analysis of patient data showed risk increases for both serious haemorrhage (HR 1.61, 95% CI 1.47 to 1.77) and ischaemic stroke (HR 1.45, 95% CI 1.26 to 1.66) with each increasing decade of age in people with non-valvular AF.¹⁶ 

The study shows that older people with non-valvular AF benefit from warfarin therapy and that the relative benefits of oral anticoagulation for preventing ischaemic stroke do not change significantly with age.¹⁶ 

Antiplatelet therapy significantly reduces the risk of ischaemic stroke in younger people (HR 0.40, 95% CI 0.22 to 0.72 at age 50 years); however, the benefits decrease with age, and antiplatelet therapy is no longer of benefit in people > 77 years.¹⁶

b Defined as people with notes of 'frequent falls', 'history of falls', 'multiple falls' or 'tendency for falls' in their medical records. Notes of 'a single fall' did not constitute high risk.

Warfarin is contraindicated in people with severe active bleeding or with conditions associated with increased risk of severe bleeding⁶ (eg, severe uncontrolled hypertension,⁶ recent gastrointestinal [GI] bleeding, genitourinary bleeding, active ulceration or severe thrombocytopenia⁶) as well as people with compliance problems (includes lack of access to INR monitoring as well as non-adherence).

The place in therapy of the newer oral anticoagulants is currently uncertain. In Australia rivaroxaban (once a day)²⁰ and dabigatran (twice a day)²¹ are approved by the Therapeutic Goods Administration (TGA) for use in prevention of stroke or systemic embolism in people with non-valvular AF.

Therapeutic Guidelines recommends these as second-line treatment options for people with non-valvular AF at moderate-to-high risk of stroke.⁴ Some international guidelines recommend both drugs as second-line,²² some as first-line alongside^23,24 or even before warfarin.^1,18 

Apixaban is not yet approved by the TGA but is approved by the US Food and Drug Administration and for use in Europe for the prevention of stroke or systemic embolism in people with non-valvular AF . 

Dabigatran, rivaroxaban and apixaban are listed on the Pharmaceutical Benefits Scheme (PBS) for the prevention of venous thromboembolism following total knee or total hip replacement.^25-27 

Rivaroxaban is also PBS-listed for the treatment of symptomatic deep vein thrombosis without symptomatic pulmonary embolism and to prevent recurrent venous thromboembolism.²⁸

Warfarin is not suitable for all; neither are the newer drugs

Warfarin is underused for many reasons, including the perceived risk of bleeding,^10,29 the need for regular monitoring and the risk of adverse interactions with other drugs and foods.²³ 

The newer oral anticoagulants address some of these concerns for people with non-valvular AF (eg, INR monitoring is not required, lower risk of ICH) but some drug interactions remain a concern.^6,20,21,30 The newer oral anticoagulants have not yet been tested in people who are unsuited to warfarin.^31-33 

Dabigatran, rivaroxaban and apixaban are contraindicated in people with severe renal impairment.^6,20,21,30

In key trials, dabigatran 150 mg (RE-LY trial) and apixaban (ARISTOTLE trial) both reduced the incidence of stroke/systemic embolism compared with warfarin based on analysis of the intention-to-treat trial populations.^31,32 

Rivaroxaban (ROCKET-AF trial) and dabigatran 110 mg (the indicated dose in Australia for people > 75 years)²¹ were non-inferior^c to, but not better than, warfarin for the incidence of stroke/systemic embolism based on analysis of the intention-to-treat trial populations.^31,33 

Participants in the warfarin arms of the rivaroxaban, apixaban and dabigatran key trials had a mean TTR^d of 55%, 62.2% and 64%,  respectively.^31-33 When warfarin was well controlled (≥ 66% TTR³⁴) dabigatran (110 mg and 150 mg) and apixaban were non-inferior to warfarin for the incidence of stroke/systemic embolism.^31,32 

Non-inferiority was not shown by rivaroxaban for incidence of stroke/systemic embolism when warfarin was well controlled.^33,35,36 Only apixaban was better than warfarin for reducing major bleeding when warfarin was well controlled.^32,34,e

Participants in the key trials all had non-valvular AF. Participants in the rivaroxaban study had at least two additional risk factors for stroke and a mean CHADS₂ score of ~3.5 whereas participants in the dabigatran and apixaban trials had at least one additional risk factor for stroke and an average CHADS₂ score of 2.1–2.2 and 2.1, respectively.^31-33 

Concomitant use of anticoagulant and aspirin was permitted in both arms of the trials, which may have affected safety outcomes.^31-33

The newer oral anticoagulants are associated with reduced incidence of ICH compared with warfarin, but absolute risk reductions in trials were small and rivaroxaban and dabigatran (150 mg) had increased incidences of GI bleeds (Table 5).^31-33 Incidence of death after ICH was similar with warfarin and dabigatran in trials.³⁷

^c Non-inferior: the effect of a new drug is not worse than that of another drug by more than a specified margin.

^d Time in therapeutic range (TTR): the percentage of time when a person has an INR within the prescribed range, when stroke and bleeding risk is lowest. For people with non-valvular AF this is 2–3.

^e In the ARISTOTLE trial, bleeding outcomes were assessed in patients who received at least one dose of the study drug and events that occurred from the time the patients received the first dose of the study drug through 2 days after they received the last dose.

^f Number needed to treat to prevent one intracranial haemorrhage or number needed to harm to cause one extra major gastrointestinal bleed in 1 year by using newer oral anticoagulants compared with warfarin.

^g Differences in events compared with warfarin non-significant.

Point-of-care testing reduces some of the burden of laboratory-based INR testing and may be useful in rural or remote areas where access to laboratory testing is difficult.³⁸ A recent meta-analysis showed that point-of-care testing (where patients self-tested or self-managed anticoagulation):³⁹ 

• significantly reduced incidence of thromboembolism
• resulted in similar or better INR control (TTR) 
• was associated with a similar incidence of major haemorrhage and death compared with primary care or anticoagulation clinic INR testing.
  

Subset analysis for patients with AF showed no significant difference for incidence of thromboembolism or major haemorrhage.³⁹ 

A previous meta-analysis comparing anticoagulation monitoring using a point-of-care testing device with laboratory analysis showed similar results, although use of point-of-care testing devices significantly reduced mortality and improved TTR.⁴⁰ 

Not all patients with non-valvular AF will be suitable for point-of-care testing (patients need visual acuity, manual dexterity and cognitive abilities) and how well its accuracy compares with laboratory results is uncertain.⁴¹ Medicare does not currently fund point-of-care testing.

The need for anticoagulant substitution with heparin depends on the patient’s thromboembolic risk.

In people at low risk of stroke, stop warfarin 3–5 days before procedures when there is a high risk of bleeding and resume warfarin once adequate haemostasis is achieved.⁴ 

For people with high risk of thromboembolism undergoing procedures associated with a high risk of bleeding, anticoagulant substitution with a therapeutic dose of unfractionated heparin or low molecular weight heparin is often required (see Therapeutic Guidelines).⁴ 

Some procedures associated with a low risk of bleeding (eg, simple dental procedures) do not require warfarin to be stopped if the INR is within 2–3.⁴²

Stop dabigatran and rivaroxaban at least 1–3 days before any surgery, or earlier for people at higher risk of bleeding, those with renal impairment and those undergoing procedures with a high risk of bleeding.^6,20,21 Stop apixaban at least 3 days before surgery.⁶ 

Expert opinion suggests that a substitute anticoagulant would not be required if anticoagulation were stopped for periods up to 48 hours for most procedures in people at low bleeding risk and with normal renal function.⁴³ Dabigatran and rivaroxaban can also be restarted when adequate haemostasis has been restored.¹

If heparin is needed, dabigatran, rivaroxaban or apixaban can be restarted after the operation when the next dose of heparin would have been given. As they have an immediate onset of action, crossover therapy with the heparin is not needed.⁴ 

No evidence-based guidelines for the dental management of patients receiving these agents are currently available.

• Prof David Brieger, Concord Clinical School, University of Sydney & ANZAC Research Institute, Concord Hospital, Sydney, NSW
  
• Dr Jenny Curnow, Staff specialist, ANZAC Research Institute Concord Repatriation General Hospital, Sydney, NSW
  
• Assoc Prof John Worthington, Faculty of Medicine, University of NSW & Ingham Institute, Liverpool Health Service, Sydney, NSW
  

Reviewers

• Dr John Dowden, Editor, Australian Prescriber
  
• Dr Graham Emblen, GP, Toowoomba, QLD
  
• Dr Oliver Frank, GP, Hillcrest, SA
  
• Benafsha Khariwala, Editor, Therapeutic Guidelines
  
• Deborah Norton, QUM Pharmacist, West Vic DGP