The results of ROCKET-AF, which showed that the direct Factor Xa inhibitor rivaroxaban (Xarelto, Bayer Healthcare) was non-inferior to the prevention of stroke or systemic embolism in patients with atrial fibrillation, have now been published online in The New England Journal of Medicine. ROCKET-AF co-chair Keith Fox, from the Centre for Cardiovascular Science at the University of Edinburgh, UK, talks to Cardiac Rhythm News about the study and its implications.
How do direct factor Xa inhibitors, such as rivaroxaban, work?
Factor Xa is a key step in the coagulation pathway and by inhibiting Xa, it is an efficient way of reducing clotting. One molecule of FXa can catalyse the formation of over a thousand molecules of thrombin.
What advantages could the new anticoagulants (eg, direct factor Xa inhibitors and direct thrombin inhibitors) have over warfarin?
Warfarin is difficult to control (and has to be monitored with regular blood tests) because of the way it interacts with food substances (eg brassica), alcohol and other medications. Control is even more difficult in patients with heart failure. As a result, many patients that should be on warfarin for stroke risk are not on the drug. However, the new anticoagulants do not have these same issues with control – there is no need to monitor them in the same way.
Why did you decide to analyse the data in ROCKET-AF in a variety of ways?
The trial was designed as a non-inferiority trial and therefore, the most appropriate analysis was the one that was done (on treatment). If one included people with periods off treatment, this would tend to make a “non-inferiority” result more likely. By design, having established non-inferiority, we then tested for superiority on treatment [which showed that rivaroxaban was significantly superior to warfarin while patients were taking randomised treatment] and then did the intention-to-treat analysis [which found no significant difference between patients receiving rivaroxaban and those receiving warfarin] that included people in the post study period (total intention-to-treat period was 117 days beyond the on-treatment period).
In a recent joint consensus statement, the German Atrial Fibrillation Competence Network (AFNET) and the European Heart Rhythm Association (EHRA) said there a need is for comprehensive information, such as side effects and drug-drug interactions, on the new anticoagulants. Do we have this information for rivaroxaban? If not, how close are we to getting it?
We are increasingly getting this information. More than 25,000 patients have been studied in randomised trials of rivaroxaban, and it licensed in many countries and is widely used for the treatment and prevention of deep vein thrombosis.
Assuming that the new anticoagulants, such as rivaroxaban, are approved in both Europe and America for the prevention of stroke in patients with atrial fibrialltion, does this spell the end of warfarin?
If these drugs are approved, patients and doctors will then have several treatment options. The first priority for these new drugs will be for those who already have difficulty with warfarin and those who are anticipated to have difficulty with warfarin. Eventually, also considering costs, the new agents may replace warfarin.
