Bristol-Myers Squibb/Pfizer’s oral Factor Xa inhibitor apixaban can more than halve the risk of stroke or systemic embolism compared with aspirin in patients with atrial fibrillation (AF) who cannot take warfarin, the results of the Phase III AVERROES trial have shown.

In June the two companies, which forged a worldwide collaboration to develop and commercialise apixaban in 2007, said they were halting the AVERROES (Apixaban Versus Acetylsalicylic acid to Prevent Strokes) trial after a predefined interim analysis by the Data Monitoring Committee showed “clear evidence of a clinically important reduction” in stroke and systemic embolism in AF patients considered intolerant of, or unsuitable for, vitamin K antagonist therapy.

Now the partners have put some numbers on that outcome, confirming apixaban’s potential as one of the new batch of drugs that will compete against standard warfarin therapy and aspirin in the market for stroke prevention in AF patients.

That market could eventually be worth anything from US$10-20 billion per year, analysts estimate. According to BMS/Pfizer, 40-50% of AF patients at moderate or high risk of stroke do not receive warfarin, due to concerns about bleeding, difficulty in managing or maintaining therapeutic dosing, or interference from other prescription drugs.

It was notable, then, that in the AVERROES trial the safety profile of apixaban, and specifically its potential to cause major bleeding, compared favourably with aspirin. The top-line outcomes were as follows: the primary efficacy endpoint (stroke or systemic embolism) occurred in 1.6% of patients in the apixaban group and 3.6% of patients in the aspirin group, giving a statistically significant relative risk reduction of 54% (p<0.001) for apixaban. 

The annual rate of stroke, which was a component of the primary endpoint, was 1.5% for apixaban and 3.3% for aspirin, a statistically significant relative risk reduction of 52% (p<0.001). The annual event rates for major bleeding were 1.4% for apixaban and 1.2% for aspirin, a margin that was not statistically significant (p=0.56). Overall mortality rates were 3.4% and 4.4% for apixaban and aspirin respectively.

Conducted in 36 countries and co-ordinated by the Population Health Research Institute (PHRI) at McMaster University and Hamilton Health Sciences in Canada, the AVERROES trial involved 5,600 AF patients regarded as intolerant of, or unsuitable for, therapy with a vitamin K antagonist such as warfarin. Patients were randomised to either apixaban 5mg twice daily or aspirin 81-324mg once daily.

"Truly impressive”

Presenting the AVERROES data at the European Society of Cardiology (ESC) 2010 Congress in Stockholm, Sweden, principal investigator Dr Stuart Connolly from the PHRI described the results as “truly impressive”.

The reduction in stroke and systemic embolism with apixaban versus aspirin “is very important and the increased risk of haemorrhage is small”, Dr Connolly commented. “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.”

Leading the discussion of the results at the ESC Congress, Harald Arnessen from Oslo University Hospital Ullevål in Norway concurred, calling AVERROES a “landmark study”.
The outcomes will obviously have an impact on guidelines for antithrombotic treatment in AF patients and use of aspirin in these patients is likely to be reduced drastically, Arnessen suggested, although he did add that compliance would be a challenge with twice-daily dosing of apixaban.

The ongoing ARISTOTLE trial is assessing the safety and efficacy of apixaban versus warfarin in patients who qualify for treatment with the vitamin K antagonist. The lead indication for apixaban is prevention of venous thromboembolism following orthopaedic surgery.