New Anticoagulants as an Alternative to Aspirin in Atrial Fibrillation - Implications of the Apixaban versus Acetylsalicylic Acid to Prevent Strokes (AVERROES) Trial

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia¹ and increases the risk of stroke and thromboembolism, on average, fivefold.² Strokes in AF are generally more severe and associated with greater mortality and disability than strokes from other causes.³ Prevention of stroke and thromboembolism is therefore an important part of AF management. Guidelines have, until now, recommended that patients with AF receive some form of antithrombotic therapy, either a vitamin K antagonist (VKA) or aspirin, with a preference for anticoagulants in most cases.⁴ However, such current treatments are suboptimal and despite recommendations, many patients do not receive adequate thromboprophylaxis.⁴

Apixaban is a new oral anticoagulant inhibiting activated coagulation factor X (FXa).⁵ The first report on the efficacy of apixaban in atrial fibrillation was recently given in the Apixaban versus acetylsalicylic acid to prevent strokes (AVERROES) trial.⁶ This is the first report of one of the new anticoagulants currently being developed as an alternative to aspirin in patients deemed not suitable for VKAs.

As a brief foreword to this article, I will here briefly review the practical relevance of these initial clinical data. AVERROES (NCT00496769) was a randomised, double-dummy, double-blind study to assess the superiority of apixaban 5 mg bid versus aspirin (acetylsalicylic acid) (81–324 mg/day) for the prevention of stroke in 5,599 patients with AF and at least one additional risk factor for stroke, who had failed, or were considered unsuitable for, VKA treatment.⁶ In April 2010, the Data and Safety Monitoring Board recommended early study termination because of clear benefit in favour of apixaban. The median duration of follow-up was 1.5 years. The primary outcome was stroke or systemic embolism. There were 51 primary outcome events in those randomised to apixaban (1.6 %/year) and 113 in those randomised to aspirin (3.7 %/year) (hazard ratio [HR] 0.45, 95 % confidence interval [CI] 0.32–0.62; p<0.001). Mortality rates were 3.5 %/year on apixaban and 4.4 %/year on aspirin (HR 0.79, 95 % CI 0.62–1.02; p=0.07). 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.⁶ Thus, a clear superiority of apixaban over aspirin was shown in terms of efficacy, with comparable safety. I will here briefly discuss the clinical implications of the trial.

The Apixaban versus Acetylsalicylic Acid to Prevent Strokes (AVERROES) Trial in Context

One previous trial in a quite similar patient population, Effect of clopidogrel added to aspirin in patients with AF (ACTIVE A),⁷ had tested the superiority of aspirin plus clopidogrel. In such patients, aspirin plus clopidogrel reduced the rate of major vascular events, in particular stroke, versus aspirin alone (relative risk [RR] 0.72, 95 % CI 0.62–0.84), but with an increased risk of major haemorrhage (RR 1.56, 95 % CI 1.28–1.89) and therefore with uncertain clinical benefit.7 AVERROES has therefore shown that the new oral anti-Xa inhibitor apixaban is clearly better than aspirin in terms of efficacy, with surprisingly similar safety. Based on the indirect comparison with ACTIVE A, one is clearly forced to conclude that apixaban is, at the time of writing, the best alternative to aspirin ever found in patients deemed unsuitable for VKAs.

Strengths of The Apixaban versus Acetylsalicylic Acid to Prevent Strokes (AVERROES) Trial

The strong points and important messages of the study are therefore:

• the randomised, double-blind, double-dummy design of the study;
• the clear favourable outcome, with better efficacy and similar safety of apixaban versus aspirin;
• reassuring news on the tolerability of the twice daily dosing of apixaban given here; and
• a confirmation of the fact that, in general, all new anticoagulants that completed or are completing phase III programmes (dabigatran etexilate,⁸ rivaroxaban⁹ and apixaban) all have an advantage in the reduction of intracranial bleeds.

Possible Criticisms of The Apixaban versus Acetylsalicylic Acid to Prevent Strokes (AVERROES) Trial

The main possible criticism of AVERROES revolves around the inclusion criteria for this study. Patients were eligible if they were 50 years of age or older and had AF documented in the six months before enrolment or by 12-lead electrocardiography on the day of screening. Patients also had to have at least one of the following risk factors for stroke: prior stroke or transient ischaemic attack (TIA), an age of 75 years or older, arterial hypertension (receiving treatment), diabetes mellitus (receiving treatment), heart failure (New York Heart Association class II or higher at the time of enrolment), a left ventricular ejection fraction of 35 % or less or documented peripheral artery disease.

In addition, patients could not be receiving VKA therapy, either because this had already been demonstrated to be unsuitable for them or because it was expected to be unsuitable. The reasons that VKA therapy was unsuitable for the patient had to be documented on the study case report forms. Of the 5,599 patients enrolled, reasons for the unsuitability for VKA therapy included:

• the assessment that the International Normalised Ratio (INR) could not be maintained in the therapeutic range;
• adverse events not related to bleeding during VKA therapy;
• a serious bleeding event during VKA therapy;
• the assessment that INR could not be, or was unlikely to be, measured at the requested intervals;
• expected difficulty in contacting the patient for an urgent change in the dose of VKAs;
• uncertainty about the patient’s ability to adhere to instructions regarding VKA therapy;
• concurrent medications that could alter the activity of VKAs;
• concurrent medications whose metabolism could be affected by VKAs;
• the assessment that the patient would be unable or unlikely to adhere to restrictions on factors such as alcohol and diet;
• hepatic disease;
• mild cognitive impairment, heart failure or cardiomyopathy and ‘other factors that could be associated with increased risk of VKA use’;
• a CHADS₂ score of one or less;
• VKA therapy not recommended by the physician;
• other characteristics indicating risk of stroke too low to warrant treatment with VKAs;
• the patient’s refusal to take VKAs; and
• ‘other reasons’.

All of these reasons can be grouped in three broad categories:

• an assessment by the physician that thromboembolic risk (despite a CHADS₂ score of at least one being an inclusion criterion) was too low to warrant VKA therapy (11–12 %);
• the patient’s refusal to take VKAs as the only reason for unsuitability (about 15 %); and
• physician-related assessment of unsuitability: about three-quarters of cases.

One may question each of these choices: current European Society of Cardiology (ESC) guidelines, for example, underscore the opportunity of using VKAs also in low-risk categories (CHADS₂-VASc₂=1)¹⁰ because of the demonstration that patients in these categories also gain from the use of a VKA versus antiplatelet agents alone.¹¹ Therefore, the category of ‘patients at too low risk to warrant VKA use’ is currently shrinking more and more. A patient’s refusal to take VKAs is clearly strongly influenced by the ability of the doctor to convey the message of the importance of a therapy to avert stroke. The vast majority of ‘unsuitability’ was the physician’s perception of an uncertain net clinical benefit (risk–benefit balance) of VKA therapy, which is to a large extent subjective and modifiable by other interventions. Yet these proportions are reflected in the current underuse of VKAs in patient registries. In the National Anticoagulation Benchmark Outcomes Report (NABOR), retrospectively evaluating practices in hospitalised patients with AF (n=945), out of 86 % of patients eligible for warfarin, only 55 % actually received it.¹² This proportion was similar for both academic and community hospitals. In the Euro Heart Survey on AF, only 67 % of patients eligible for VKAs were actually prescribed them and 7 % of eligible patients did not receive any form of antithrombotic treatment.¹³ Therefore, the population included in AVERROES represents an existing population in whom, for several reasons, VKAs are, as a matter of fact, not used, despite overwhelming evidence of their efficacy.

Conclusions

In summary, in patients considered ‘unsuitable’ for VKAs for whatever reason, a wide category of patients always documented in registries, apixaban is a therapeutic option more effective than, and as safe as, aspirin itself, with a very low rate of major bleeding complications and especially of intracranial haemorrhage. Apixaban is also being tested in the on-going Apixaban for the prevention of stroke in subjects with AF (ARISTOTLE, NCT00412984) trial, which is a phase III randomised, double-blind, double-dummy study testing the non-inferiority of apixaban versus warfarin for the composite of stroke and systemic embolism in ≈18,000 patients with AF. Patients are required to have at least one additional risk factor for stroke, including age ≥75 years, previous stroke, TIA or systemic embolism and diabetes. The study has been completed and the results will be presented in August 2011. This study will tell us whether apixaban is also an alternative to VKAs in patients deemed ‘suitable’ for these older drugs.