Preventing ischaemic stroke in atrial fibrillation

Chair UKCPA HAT Committee

Lead Clinical Pharmacist,

London Bridge Hospital, London, UK

Email: [email protected]

Atrial fibrillation (AF) is the most common cardiac arrhythmia.(1) It currently affects more than one million people in the UK.(2) Because the risk of AF increases with age, as life expectancy is increasing, it is estimated that the AF population will approximately double by 2050.(3)

AF is a major risk factor for stroke and systolic embolism.(1) It causes an almost fivefold independent increase in the risk of ischaemic stroke.(1) It is estimated that 15% of all strokes in the UK are directly attributable to AF – this equates to approximately 12,500 AF-related strokes each year.(4) AF-related strokes tend to be more severe than non-AF related strokes, with a 20% increased likelihood of death and 60% increased likelihood of disability compared with non-AF strokes.(2) They are therefore associated with a longer hospital length of stay.(2) AF-related strokes can not only have a potentially devastating impact on people and their families, but they can also present a significant cost burden.(5) Each AF-related stroke costs an average £11,900 in the first year.(6) The National Health Service (NHS) spends £4.6 billion annually on stroke care.(6) Therefore, prevention of AF-related stroke is not only vital in improving patient outcome but is also a cost-effective use of resources.(2)

The stroke risk associated with AF depends largely on comorbid factors and there are a number of systems for evaluating this risk. One of the simplest is called the CHADS2 system. A history of chronic heart failure, hypertension, age >75 years and diabetes each receives a score of one. A history of stroke or transient ischaemic attack is scored two. The patient’s total score is then determined. A score of 2 or more indicates that the patient is at high risk of stroke. A score of 1 indicates an intermediate degree of risk whereas a score of 0 indicates that the patient is at low risk of stroke. The CHADS2 score obtained is therefore individual to each patient and will determine the choice of preventative treatment chosen.

The use of vitamin K antagonists (VKA) is the most effective standard therapy to prevent stroke and systemic events in patients with AF.(1) Until recently, VKAs were the only available oral anticoagulants, and were recommended as the gold standard therapy.(1) Warfarin, the most commonly used VKA, reduces the risk of stroke by approximately two-thirds in patients with AF.(7) However, despite recommendations, many patients do not receive adequate anticoagulation. This is because there are several limitations to warfarin use. Its narrow therapeutic window and significant inter/intra individual variability poses the need for regular monitoring, leading to ineligibility in some patient groups. It is also affected by diet, drugs and alcohol resulting in lifestyle restrictions.(8)

The National Institute for Health and Care Excellence (NICE) in 2006 estimated that 46% of patients who should have been on warfarin for AF were not receiving it.(9) More recent data from Guidance on Risk Assessment and Stroke Prevention for AF (GRASP-AF) shows only 54% of patients with AF and a CHADS2 score of ≥1 receive anticoagulation.(10) Time out of therapeutic International Normalised Ratio (INR) range is associated with increased incidence of ischaemic stroke, bleeding and mortality.(11,12) Generally, patients receiving warfarin only remain within the target INR range 52–68% of the time.(11,13,14) Aspirin is often used as an alternative to warfarin. It reduces the risk of stroke in patients with AF by about 20% and is commonly used in patients for whom warfarin is unsuitable.(15)

As a consequence of the limitations related to warfarin treatment, attempts have been made to produce novel oral anticoagulant drugs targeting specific components of the coagulation cascade.(1) The process of coagulation is complex and there are many possible targets for new drugs. Thrombin (factor IIa) plays a key role in the generation of a thrombus. Therefore, inhibiting thrombin activity and/or its generation has been a major target in the search for novel anticoagulant agents.(1) The early research approach focused on inhibition of thrombin activity using direct thrombin inhibitors. Another approach is the inhibition of thrombin production by blocking the upstream proteases in the blood coagulation cascade, such as factor Xa (Figure 1).

To date, NICE has approved three new oral anticoagulants (NOACs) for the prevention of stroke in AF.(16–18) Dabigatran, a direct thrombin inhibitor, was the first to receive a UK license for this indication in April 2008. Rivaroxaban followed in October 2008. It is a factor Xa inhibitor recommended by NICE as an option for the management of stroke prevention in AF. Apixaban is the latest oral agent to receive a UK licence for this indication. It is a potent, oral, direct and highly selective factor Xa inhibitor. By inhibiting factor Xa, apixaban prevents thrombin generation and subsequent thrombus development. It has an oral bioavailability of approximately 50%, a half-life of 9–14 hours and achieves its peak plasma level three hours after oral administration.(19) Apixaban at doses of 5mg and 2.5mg twice daily has a European marketing authorisation for the ‘prevention of stroke and systemic embolism in adult patients with non-valvular AF, with one or more risk factors, such as prior stroke or transient ischaemic attack, age 75 years or older, hypertension, diabetes mellitus, or symptomatic heart failure’.(19)

Two randomised controlled trials have examined the efficacy of apixaban (Table 1).

In the ARISTOTLE trial(20) apixaban was compared with warfarin for the prevention of stroke or systemic embolism in patients with AF and at least one additional risk factor for stroke. This was a double-blind, double-dummy, trial in 18,201 patients with non-valvular AF.(20) Patients were randomised to either apixaban at a dose of 5mg twice daily (2.5mg twice daily with ≥two of the following criteria: age ≥80 years, body weight ≤60kg, or serum creatinine level ≥150µmol/l), or warfarin to a target INR of 2–3. Warfarin was within the therapeutic range 66% of the study time.(20)

The primary efficacy outcome was the composite of stroke and systemic embolism. The annual event rates were 1.27%/year on apixaban and 1.6%/year on warfarin. For every 1000 patients treated for 1.8 years, apixaban prevented six strokes, 15 major bleeds, and eight deaths compared with warfarin. Apixaban not only proved to be non-inferior (hazard ratio (HR) 0.79; 95%CI 0.66–0.95; p<0.001 for non-inferiority) but also superior to warfarin (p=0.01 for superiority) in the intention-to-treat population.(20) Thus ARISTOTLE showed that apixaban in patients with non-valvular AF and a mean CHADS2 score of 2.1 was superior to warfarin in the prevention of stroke or systemic embolism, and resulted in lower mortality.(20)

However, along with numerous strengths, there were some limitations to the ARISTOTLE trial. First, the observation period of 1.8 years did not provide information on the long-term effects of apixaban. However, the benefits remained consistent over the study period, so that ‘wearing off’ in the long-term is not likely.(21) Second, the drug is not yet studied in patients with severe renal insufficiency (serum creatinine of >221µmol/l OR calculated creatinine clearance of <25ml/min).(21) Third, there is little known about possible interactions with concomitant medications. However, in vitro studies have demonstrated that metabolic interactions are unlikely.(21)

The AVERROES trial compared apixaban with aspirin for the prevention of stroke in AF.(22) This was the only trial testing one of the NOACs as an alternative to aspirin. AVERROES was a randomised, double-dummy, double-blind study assessing the superiority of apixaban (5mg twice daily) against aspirin (81–324mg/day) for the prevention of stroke in 5599 patients with AF and at least one additional risk factor for stroke who had failed, or were considered unsuitable for treatment with vitamin K antagonists.(22) The primary outcome was stroke or systemic embolism. There were 51 events in those randomised to apixaban (1.6%/year) and 113 in those randomised to aspirin (3.7%/year) (HR: 0.45, 95%CI: 0.32–0.62; p<0.001). Mortality rates were 3.5% per year on apixaban and 4.4% per year on aspirin (HR: 0.79, 95%CI:0.62–1.02; p=0.07). For every 1000 patients treated for 1 year, apixaban prevented 21 strokes, 13 fatal or disabling strokes, and 33 cardiovascular hospitalisations compared with aspirin.(22) Thus, clear superiority of apixaban over aspirin was shown in terms of efficacy. In April 2010, the data and safety monitoring board recommended early study termination because of clear benefits shown in favour of apixaban.

The safety of apixaban was evaluated in the ARISTOTLE and AVERROES studies with a total of 11,284 patients exposed to apixaban 5mg twice daily and 602 patients to 2.5mg twice daily.(20,22)

The primary safety endpoint in the ARISTOTLE trial was major bleeding. This occurred in 327 patients in the apixaban arm (2.13%/year) and 462 patients in the warfarin arm (3.09%/year; HR 0.69; 95%CI 0.60–0.80; p<0.001).

Intracranial bleeding, other location bleeding, major or clinically relevant non-major bleeding and any bleeding were more common in the warfarin arm.(20) The incidence of death from any cause was significantly lower in the apixaban arm (apixaban versus warfarin 3.52%/year versus 3.94%/year; HR 0.89; 95%CI 0.80–0.99; p=0.047).(20) Thus, ARISTOTLE showed that apixaban resulted in less bleeding and lower mortality than warfarin.

In the AVERROES trial, there were 44 (1.4%/year) major bleeds on apixaban and 39 (1.2%/year) on aspirin (HR 1.13. 95%CI 0.74–1.75; p=0.57). There were 11 intracranial bleeds on apixaban and 13 on aspirin.(22) Mortality rates in AVERROES were 3.5%/year on apixaban and 4.4%/year on aspirin (HR 0.79, 95%CI 0.62–1.02; p=0.07).(6) Thus, apixaban displayed comparable safety with aspirin.

There are no data currently available directly comparing apixaban with dabigatran or rivaroxaban.

The annual cost of apixaban treatment is £799.50. This compares with £764.40 for rivaroxaban and £799.50 for dabigatran.(23) A recent economic evaluation (which took into account the cost of treating events such as bleeds and strokes) found that apixaban was likely to be less cost effective than dabigatran, but more so than rivaroxaban.(24) The analysis was very sensitive to drug cost, and assumed that treatment with apixaban 5mg twice daily would be twice as costly as treatment with 2.5mg twice daily (hence £6.86 per day). However, the true price of apixaban 5mg is £2.20 per day, therefore apixaban will be more cost-effective than indicated by the model.(23)

A drug is considered to be cost effective as compared to a comparator if the incremental cost effectiveness ratio (ICER) is below £20,000 per quality-adjusted life year (QALY) gained. The NICE Evidence Review Group has deemed apixaban cost effective when compared with warfarin. They have calculated an ICER for apixaban compared with warfarin of £12,757 per QALY gained.(18) However, apixaban is currently considerably more expensive than warfarin, even when taking into account warfarin monitoring costs, which have been estimated at anywhere from £115 to £415 per patient per year.(16) Warfarin clinics will still need to be maintained, and running costs may not be reduced substantially by switching some patients to the newer agents. Therefore, apixaban is less likely to be cost effective in patients who are currently well controlled on warfarin.

The current NICE guidance on the management of atrial fibrillation(25) pre-dates the era of the NOACs. Updated NICE guidance is expected in 2014. To address the current lack of a national clinical guideline recommending up-to-date, evidence-based best practice in anticoagulation throughout the NHS, clinicians should follow the recommendations of the 2012 European Society of Cardiology (ESC) Guidelines on the Management of Atrial Fibrillation.(26) These guidelines advocate the use of the NOACs as being broadly preferable to warfarin for the vast majority of patients with non-valvular AF.(26)

In its recent appraisal, NICE has recommended the use of apixaban as an option for stroke prevention in AF, in patients with additional stroke risk factors.(18) However, owing to the high relative cost of treatment, the UK Cardiac and Stroke Networks have issued specific criteria for use of apixaban to minimise cost and maximise benefit in selected populations.

They have advised that apixaban could be recommended in patients with a high stroke risk (CHADS2 ≥1) who are unable to tolerate warfarin due to severe adverse effects or in patients for whom warfarin is contraindicated because of allergy. It may also be useful for patients who are currently treated with warfarin but who have difficulty maintaining their INR in the therapeutic range. However, they have clearly stated that patients who are currently stable on warfarin should not be considered for a switch to apixaban.(27)

One of the advantages of the NOACs may translate into a disadvantage in clinical practice. The non-requirement for regular monitoring also provides a lack of laboratory monitoring in cases of bleeding or thrombosis. As a result, adherence to treatment cannot be determined as it can with warfarin.

One of the advantages of warfarin is the ability to reverse its anticoagulant effects in cases of bleeding using vitamin K.

However, there is currently no antidote available to reverse the effects of any of the NOACs in the event of overdose or major bleeding. Prothrombin complex concentrate has demonstrated efficacy for reversing factor Xa inhibition in rats(28) and in healthy human subjects.(29) However, until a suitable agent is clinically proven, given apixaban’s short elimination half life, a supportive approach is recommended in cases of overdose or major bleeding.

Apixaban is a factor Xa inhibitor licensed for the prevention of stroke in AF. Its safety and clinical effectiveness have been well documented in the ARISTOTLE and AVERROES trials. It has demonstrated superiority to warfarin and aspirin in the prevention of stroke or systemic embolism in addition to a lower mortality rate. NICE have deemed apixaban as a cost-effective option compared with warfarin for the prevention of stroke in AF with an ICER of £12,757 per QALY gained. However, owing to its high relative cost, apixaban is less likely to be cost effective in patients who are currently well controlled on warfarin; therefore, such patients should not normally be considered for a switch to apixaban. Ongoing challenges that need to be addressed include the inability to assess adherence due to the non-requirement for frequent monitoring and the lack of an available antidote.

• Apixaban is a potent, oral, direct and highly selective factor Xa inhibitor. By inhibiting factor Xa, it prevents thrombin generation and subsequent thrombus development.
• Apixaban has demonstrated superior efficacy to warfarin and aspirin in the prevention of