The AVERROES (Apixaban Versus Acetylsalicylic acid (ASA) to Prevent Strokes) trial randomized 5600 AF patients who were unable to take warfarin to receive either aspirin or apixaban, a Factor Xa inhibitor. (Another trial still underway, ARISTOTLE, is a direct comparison of warfarin and apixaban in AF.) AVERROES was stopped early after the Data Monitoring Committee found clear evidence of clinically important benefit and an acceptable safety profile.
Stuart Connolly reported a reduction in the primary endpoint of the study, a composite of stroke or systemic embolism, from 3.6% per year in the aspirin group to 1.7% per year in the apixaban group (HR 0.46, CI 0.33-0.64, p<0.001). The rate of major bleeding was 1.4% per year on apixaban and 1.2% per year on aspirin (HR 1.14, CI0.74–1.75, p=0.56). Hemorrhage stroke occurred at a rate of 0.2% per year in both treatment groups.
Connolly calculated that for every 1000 patients treated with apixaban for one year instead of aspirin 18 strokes, 10 deaths, and 31 CV hospitalizations could be prevented, at a cost of 2 major bleeds.
Commenting on the results in an ESC press release, Connolly said: “The results of AVERROES are truly impressive. The reduction in stroke and systemic embolism is very important and the increased risk of haemorrhage is small. It appears that apixaban will be an excellent treatment for the many patients with atrial fibrillation who are unsuitable for warfarin. These findings will reduce the burden of stroke in society.”
The designated discussant at the Hot Line presentation, H. Arnesen, said AVERROES was a “landmark study that will affect guidelines,” and he predicted that aspirin use would diminish after apixaban becomes available.
Here is the ESC press release:
AVERROES trial terminated early: apixaban associated with “important” relative risk reduction for stroke and systemic embolism in AF
Stockholm, Sweden, 31 August: The phase 3 AVERROES (Apixaban Versus Acetylsalicylic acid (ASA) to Prevent Strokes) trial, designed to show the superiority of apixaban over aspirin for the prevention of stroke or systemic embolism in high-risk atrial fibrillation patients unsuitable for treatment with a vitamin K antagonist (warfarin), was terminated early following a recommendation from the Data Monitoring Committee. Final study visits took place between 1 July and 15 August this year.
A predefined interim analysis had shown clear evidence of a clinically important reduction in stroke and systematic embolism and an acceptable safety profile for apixaban compared to aspirin. The principal investigator, Dr Stuart Connolly from Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada, and the study’s sponsors accepted the recommendation to terminate the trial.
AVERROES was a double-blind randomised trial which recruited 5600 patients with atrial fibrillation (mean age 70 years) demonstrated or expected to be unsuitable for treatment with a vitamin K antagonist (because of difficulty in controlling treatment effect, increased risk of haemorrhage, patient refusal to take warfarin or intermediate stroke risk). So far, aspirin is the only effective treatment for stroke prevention in patients unsuitable for warfarin.
Apixaban, a Factor Xa inhibitor, has already been investigated for the prevention of deep vein thrombosis, following orthopaedic surgery, and after acute coronary syndrome – but not so far in patients with atrial fibrillation. The AVERROES trial compared the effects of apixaban and aspirin in these patients. Another trial, ARISTOTLE (not yet completed) is studying apixaban against warfarin in patients suitable for warfarin.
The AVERROES study was performed at 520 sites worldwide and recruitment was completed in December 2009. The primary endpoint was a composite of stroke or systemic embolism, while the primary safety endpoint was major haemorrhage. Secondary and tertiary endpoints were a composite of stroke, systemic embolism, myocardial infarction or vascular death, and total death.
At the interim analysis results showed that the annual rate of stroke or systemic embolism (the primary outcome) was 3.9% per year on aspirin and 1.7% per year on apixaban (HR 0.45, p<0.001). The rate of major haemorrhage was 1.4% per year on aspirin and 1.6% per year on apixaban (HR 1.18, p=0.33). The rate of haemorrhagic stroke was 0.2% per year in both treatment groups and there was no evidence of hepatic toxicity or other major adverse events.
Commenting on the results, Dr Connolly said: ““The results of AVERROES are truly impressive. The reduction in stroke and systemic embolism is very important and the increased risk of haemorrhage is small. It appears that apixaban will be an excellent treatment for the many patients with atrial fibrillation who are unsuitable for warfarin. These findings will reduce the burden of stroke in society.”
* Atrial fibrillation is a common heart rhythm disorder in which the upper chamber of the heart beats improperly. Patients with AF are at increased risk of stroke because of the formation of blood clots in the upper chamber. The standard therapy for the prevention of stroke and other embolic events in AF is warfarin.