The AVERROES Trial – Clinical Implications

AVERROES (NCT00496769) was a randomised, double-blind, double-dummy study to assess the superiority of apixaban 5 mg bid vs aspirin [acetyl salicylic acid, ASA (81-324 mg/day)] for the prevention of stroke in 5,600 patients with AF and at least one additional risk factor for stroke, who had failed or were considered unsuitable for vitamin K antagonist (VKA) treatment (1).
In April 2010 the Data and Safety Monitoring Board recommended early study termination because of clear benefit in favor 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% 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 apixaban (1). Thus, a clear superiority of apixaban over aspirin was shown in terms of efficacy, with comparable safety. We will here briefly discuss the clinical implications of the trial.

AVERROES in context

One previous trial in a similar patient population, ACTIVE A (2), had tested the superiority of aspirin + clopidogrel. In such patients, aspirin plus clopidogrel reduced the rate of major vascular events, in particular stroke, vs. aspirin alone (relative risk, RR, 0.72,  95% confidence interval (CI), 0.62-0.84), but with an increased risk of major hemorrhage (RR 1.56, 95% CI, 1.28-1.89), therefore the clinical benefit was uncertain (2).

AVERROES on the other hand has shown that the new oral anti-Xa inhibitor apixaban is superior to aspirin in terms of efficacy, with surprisingly similar safety. Based on the indirect comparison with ACTIVE A, one should conclude that apixaban is, at the time of writing, the best alternative to aspirin ever found in patients deemed unsuitable for VKAs.

Strengths

Strong points and important messages of the study are:

• the favourable outcome, with better efficacy and similar safety of apixaban versus aspirin in a randomised, double-blind, double-dummy study design;
• reassuring news regarding the tolerability of the twice-daily dosing of apixaban here given;
• a confirmation on the fact that, in general, all new anticoagulants that completed or are completing phase 3 program (dabigatran etexilate (3), rivaroxaban, and apixaban) share a strong point in terms of reduction of intracranial bleeds.

Possible limitations

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 if they had atrial fibrillation that had been documented in the 6 months prior to enrollment or by 12-lead electrocardiography on the day of screening. Patients also needed to have at least one of the following risk factors for stroke: prior stroke or transient ischemic attack, be 75 years or older, arterial hypertension (receiving treatment), diabetes mellitus (receiving treatment), heart failure (New York Heart Association class 2 or higher at the time of enrollment), 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 it had been demonstrated unsuitable in their case or because it was expected to be unsuitable. The reasons that VKA therapy was unsuitable for the patient had to be documented in the study case report forms.

Of the 5599 patients enrolled, reasons for being deemed unsuitable for VKA therapy included the following:

1. Assessment that the International Normalised Ratio (INR) could not be maintained in the therapeutic range;
2. Adverse event not related to bleeding during VKA therapy;
3. A serious bleeding event during VKA therapy;
4. Assessment that INR could not or was unlikely to be measured at requested interval;
5. Expected difficulty in contacting patient for urgent change in dose of VKAs;
6. Uncertainty about patient’s ability to adhere to instructions regarding VKA therapy;
7. Concurrent medications that could alter activity of VKAs;
8. Concurrent medications whose metabolism could be affected by VKAs;
9. Assessment that patient would be unable or unlikely to adhere to restrictions on factors such as alcohol and diet;
10. Hepatic disease;
11. Mild cognitive impairment, heart failure or cardiomyopathy and, “other factors that could be associated with increased risk of VKA use”;
12. A CHADS2 score of 1 or less;
13. VKA therapy not recommended by the physician;
14. Other characteristics indicating risk of stroke too low to warrant treatment with VKAs;
15. Patient’s refusal to take VKAs; and
16. “Other reasons”.

All these reasons can be grouped in three broad categories:
• An assessment by the physician that thrombembolic risk (despite a CHADS2 score of at least 1 was an inclusion criterion) was too low to warrant VKA therapy (11-12%);
• Patient’s refusal to take VKAs as the only reason for unsuitability (about 15%);
• Physician-related assessment of unsuitability: about ¾ of cases.

One may question each of these choices:

• Current ESC Guidelines, for example, underscore the opportunity of using VKAs in low-risk categories also (CHADS2VASC2=1)(4) because of the demonstrated fact that these patients may also gain from VKAs rather than antiplatelet agents alone (5). Therefore the category of “patients at too low risk to warrant VKA use” is currently shrinking.
• Patient’s refusal to take VKAs is 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) for VKA therapy, which is to a large extent subjective and modifiable by other interventions. Yet, these proportions reflect the current underuse of VKAs in multiple registries. In the National Anticoagulation Benchmark Outcomes Report (NABOR), retrospectively evaluating practises in hospitalised patients with AF (n=945), out of 86% of patients eligible for warfarin, only 55% actually received it (6). This proportion was similar for both academic and community hospitals. In the Euro Heart Survey on AF, only 67% of patients eligible were actually prescribed VKAs, and 7% of eligible patients did not receive any form of antithrombotic treatment (7).

Therefore the population included in AVERROES represents a truly existing population in whom, for several reasons, VKAs are actually not used, despite overwhelming evidence of their efficacy.

Conclusion:

In summary, patients considered “unsuitable” for VKAs, for whatever reason, are a truly existing and wide category of patients always documented in registries. In these patients, apixaban is a therapeutic option more effective than aspirin, and as safe as aspirin, with a very low rate of major bleeding complications and of intracranial hemorrhage especially.
Apixaban is also being tested in the ongoing Apixaban for the prevention of stroke in subjects with AF (ARISTOTLE, NCT00412984), which is a phase III randomised, double-blind, double-dummy study testing the non-inferiority of apixaban vs 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 is due to be completed soon. It will tell us whether apixaban is also an alternative to VKAs in patients deemed “suited” to these older drugs.