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AVERROES: Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Strokes

Peripheral Artery Disease
Aortic Disease, Peripheral Vascular Disease, Stroke



Connolly, Stuart J

see Discussant report | read Press Release


List of Authors:
Connolly, Stuart; Eikelboom, John; Flaker, Greg; Kaatz, Scott; Avezum, Alvara; Piegas, Leopoldo; Hermosillo, Antonio; Hohnloser, Stefan; Golitsyn, Sergey; Yusuf, Salim


Patients with atrial fibrillation have an increased risk of stroke. Vitamin K antagonists (VKA), such as warfarin, are effective for reducing stroke but are associated with an increased risk of hemorrhage. In addition, the management of VKA therapy is complex, requiring frequent monitoring due to genetic variability and multiple drug and diet interactions. Many patients with atrial fibrillation cannot be maintained effectively on a VKA, others have had complications and some patients refuse to take it. For patients who are unsuitable for VKA therapy, the only alternative treatment is aspirin, which is only modestly effective. Apixaban is an investigational oral anticoagulant that selectively inhibits factor Xa. Studies in venous thromboembolism prophylaxis have demonstrated that apixaban is effective and that it has a favourable risk benefit ratio compared with low-molecular-weight heparin.

The purpose of AVERROES was to evaluate apixaban for the prevention of stroke or systemic embolism in patients with atrial fibrillation at risk for stroke who are unsuitable for therapy with a VKA. Apixaban was compared to standard therapy for these patients, which is aspirin.

AVERROES was a double-blind, randomized, active controlled evaluated of apixaban compared to aspirin. Patients with documented atrial fibrillation and at least one risk factor for stroke who are also unsuitable for therapy with a VKA were randomized 1:1 to receive either apixaban 5 mg bid (2.5 mg bid in selected patients) or aspirin (81-324 mg per day). The study was performed in 520 sites worldwide and enrollment of 5,600 patients was completed in December 2009. The Data Monitoring Committee (DMC) performed its first formal interim analysis of efficacy when 50% of expected primary outcome events had occurred and again reviewed efficacy three months later, on May 28, 2010, according to the DMC charter. Based on overwhelming evidence of efficacy against stroke or systemic embolism, together with an excellent safety profile, they recommended termination of the study so that all patients could receive open-label apixaban. This recommendation was accepted by the Steering Committee and the study sponsors.

Preliminary results are briefly described.
Treatment groups were well balanced for all baseline factors. The mean age was 70 years. The mean CHADS2 score was 2.0. 75% of patients were receiving aspirin at the time of study enrollment and 15% were receiving an oral anticoagulant. 40% had previously been exposed to a Vitamin K antagonist. The annual rate of stroke or systemic embolism (the primary outcome) was 4.0% per year on aspirin and 1.7% per year on apixaban (Hazard Ratio 0.43, 95% CI, 0.30-0.62, p=0.000004). The rate of major hemorrhage was 1.2% per year on aspirin and 1.5% per year on apixaban (Hazard Ratio 1.26, 95% CI, 0.79-2.00, p=0.33). The rate of hemorrhagic stroke was 0.2% per year in both treatment groups (Hazard Ratio 1.15, 95% CI, 0.42-3.17, p=0.79). There was no evidence of hepatic toxicity or other major adverse events.

In patients with atrial fibrillation at risk for stroke and unsuitable for therapy with a VKA, apixaban reduces the risk of stroke or systemic embolism by 57% with no significant increased risk in major hemorrhage. Apixaban offers an important advantage over aspirin for prevention of stroke in these patients.


Arnesen, Harald

see Presenter abstract



Atrial fibrillation (AF) is the most common arrhythmia in the western world today with approximately 4.5 million patients in Europe, and it has been supposed to be doubled by 2020.
AF gives rise to stroke in about 5% of untreated patients/year, translating into about 20% of all strokes.
The incidence of stroke can be reduced by about 65% with vitamin K antagonist (VKA) and about 22% with aspirin (ASA). This fits well with the pathophysiology of thrombus formation in the left atrial appendage, where the mechanism is dominated by “venous low pressure coagulation with fibrin formation” rather than by platelet activation. However, only about 50% of eligible patients are treated with vitamin K antagonist because of “treatment inconvenience” (interaction with food, alcohol, other drugs; need for regular control (INR); narrow ”therapeutic window” with risk of bleeding). ASA is regularly used in low risk patients for stroke and in patients "unsuitable for VKA".

Apixaban is a selective reversible inhibitor of factor Xa with a high oral bioavailability, rapid onset and a half-life of about 12 hours, necessitating 2 daily doses. It uses the CYP 3A4 for about 75% of its metabolism, but do not need laboratory monitoring.

AVERROES is a randomised double-blind event driven study with primary outcome the incidence of stroke or systemic embolic event during treatment with apixaban 5mg twice daily (2.5mg x 2 in special patients), (94% used 5mg x 2) or ASA 81-364 mg/day (at the discretion of the local investigator), ( 91% used ? 162mg/day). Based on the assumption that apixaban could reduce the incidence of stroke vs ASA by 35% with at least 90% power and a 1-sided ? = 0.025, and assuming a stroke rate of 3.3/100 subject-years in ASA-treated patients, 5600 patients were needed for inclusion.

The study was terminated after the first protocolled interim analyses, recommended by the DMC after approximately 50% of primary efficacy events had accrued (4 SD).

Baseline characetristics showed even distribution between the randomised groups. Age 70 years; Male gender 60%; Diabetes 20%; Prior stroke/TIA 14%; CHF 40%; Baseline ASA users 75%; VKA "unsuitable" 40%.
CHADS2 score 2.1 (mean); 0-1: 35% of patients ; 2: 35%; 3+: 30%.

The primary outcome stroke was noted in 48 patients (1.7 %/year) in the apixaban group vs. 100 (3.6 %/year) with ASA. This gives a RRR of 0.48 (95%CI 0.34-0.67), p < 0.001 in favour of apixaban, translating into NNT of 53/year to avoid 1 stroke.
The corresponding figures for major bleeding ((1 or more of the following: decrease in Hb of ? 2g/dL over a 24 hour period; transfusion of ? 2 units of packed red blood cells; bleeding in critical sites (intracranial, intraspinal, intraocular etc, and fatal bleeding) were 47 (1.6 %/year) for apixaban vs. 40 (1.4 %/year) for ASA, giving a RR of 1.18 (95%CI 0.77-1.78), p=0.45. This translates into NNH of 500/year to induce 1 major bleeding with apixaban vs. ASA.
For intracranial bleeding the figures were 13 (0.5 %/year) for apixaban and 11 (0.4 %/year) for ASA, giving a RR of 1.19 (95%CI 0.53-2.66), p=0.43.
In addition CNS vascular disorders were more frequent with ASA (4.4 %/year) than with apixaban (1.90 %/year), p>0.001.

In the opinion of the Discussant the AVERROES is a "landmark study" with impressing design, protocolled statistics, conduction and results.
The results from AVERROES emphasise the well known pathophysiological basis for the thrombotic origin in the left atrial appendage, being a typical coagulation thrombus similar to venous thrombosis with activation of the coagulation system via factor Xa and formation of a fibrin-rich product, and with only limited activation of platelets. However, the clinically important consequence of stroke is based on embolic phenomenon to an intracerebral artery.

The results from AVERROES will obviously have impact on guidelines for antithrombotic treatment in patients with AF, and the use of ASA will probably be drastically reduced in these patients.
The patients being unsuitable for VKA therapy should be clearly defined, possibly a challenging task.
With 2 daily oral doses of apixaban compliance will be a challenge, and surveillance studies (phase 4) should be undertaken.

When comparing the results from AVERROES with those of the RELY study with the factor IIa inhibitor dabigatran, and those of metaanalyses with VKA and ASA, it seems to be comparable effects with the anticoagulant principles apixaban, dabigatran and VKA, although with more bleedings with the routine use of VKA. Proper selection of patients for the various therapeutic options, as well as economic aspects of the obviously more expensive new drugs apixaban and dabigatran will probably be the basis for serious discussions to come.


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Hot Line III - Cardiovascular disease and rhythm disturbances

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.