Oral Xa inhibitors

Managing patients on warfarin therapy is an art.  There is a fine balance between achieving a supratherapeutic and subtherapeutic INR.  In addition to blindly making changes based on the INR reading, the practitioner must also take into account any changes in the patient's diet, missed doses, and any new medications among other considerations.  So far so Goude, right?

As previously covered in my entry on dabigatran, there is a demand for new oral anticoagulants that require less management and have less drug interactions than warfarin.  Dabigatran is a direct thrombin inhibitor, but there have also been a number of oral direct Xa inhibitors in development.

So where did the direct Xa inhibitors come from?  From heparin, which accelerates the inactivation of thrombin, Xa, and IXa.  Then came the low weight molecular heparins (enoxaparin, dalteparin, and tinzaparin).  The LWMHs are more selective for Xa, although they do have some anti-thrombin activity.  There is more grace with fondaparinux, which is a direct Xa inhibitor.  It is not reversible with protamine and it is specific for Xa inhibition.

Currently there are two Xa inhibitors in phase III trials in the U.S.: rivaroxaban and apixaban.

Rivaroxaban has already been approved in some European countries, but still has not been FDA approved.  For the criticism for the slow FDA approval process, I have only one thing to say: thalidomide.

Two of the major trials for rivaroxaban were the EINSTEIN and ROCKET-AF trials.  The EINSTEIN trial compared rivaroxaban to warfarin bridged by enoxaparin in the treatment of venous thromboembolism (VTE) and found that rivaroxaban prevented more events with no increased risk of bleed.  The ROCKET-AF compared rivaroxaban to warfarin for the prevention of VTE in patients with atrial fibrillation.  This trial has met the primary outcome, where rivaroxaban is non-inferior to warfarin, but superiority analyses have yet to be done.

A new multi-center RCT, AVERROES, was just published online in the New England Journal of Medicine comparing apixaban 5 mg BID to aspirin 81-324 mg in patients with atrial fibrillation that were unable to take warfarin.  Patients were followed for a year and the primary outcome was stroke or systemic embolism.

The trial was beautifully done and showed that apixaban reduced the risk of stroke or embolism in only a years time with no statistically significant increase in bleeding. 

On further inspection of the trial, I saw that 65% of patients taking aspirin were only taking 81 mg and about 26% were taking 162 mg.  I am more impressed that there was no associated increased risk of bleed compared to aspirin, rather than apixaban is more efficacious in stroke prevention than baby aspirin.

ARISTOTLE is an ongoing non-inferiority trial comparing apixaban to warfarin in patients with atrial fibrillation.  The results to this trial may offer more insight into apixaban than the AVERROES trial.

The ADVANCE trial(s) with apixaban were more impressive.  In this trial, apixaban was compared to enoxaparin for prophylaxis of VTE after a hip replacement.  Apixaban showed an absolute risk reduction of 2.5% with no increased risk of bleed.

Even if or when these drugs become FDA approved, it will take a lot more than FDA approval to replace warfarin.  Undoubtably the market is large; warfarin is difficult to manage, in some patients especially more than others.

Dabigatran, for example, still has a long way to go before it comes close to replacing warfarin.  Problems with dabigatran in clinical practice include high rates of dyspepsia, 30 day expiration, and high variability in absorption between patients.  Rivaroxaban has been shown to have a more predictable absorption between patients but it will be interesting to see what kinds of challenges for the medication may arise when/if it becomes available on the market.

One of the greatest questions with the new oral anticoagulants- dabigatran, rivaroxaban, and apixaban- is if they are more cost-effective than warfarin.  Are the costs of these medications off set by the decreased monitoring associated with them?

This is an exciting time for anticoagulation.  Unfortunately for now, we will just have to wait and see what happens.

This entry is also in reference to Jean-Paul Goude, whose work I have always admired, after being lucky enough to randomly buy his work "So far so Goude" at Club Monacco for $10... and it was worth every penny.


References:

Bauersachs R et al.  Oral rivaroxaban for symptomatic venous thromboembolism.  The New England Journal of Medicine 2010; 363:2499-2510.

O'Riordan M.  Off orbit? ROCKET-AF: rivaroxaban non-inferior to warfarin, but superiority analyses at odds.  The Heart 2010; available at http://www.theheart.org/article/1148785.do.  Accessed 02/23/2011.

Lassen MR et al.  Apixaban versus enoxaparin for thromboprophylaxis after hip replacement.  New England Journal of Medicine 2010; 363(26):2487-2498.

Connolly SJ et al. Apixaban in patients with atrial fibrillation.  The New England Journal of Medicine; published online 02/10/2011.  Accessed 02/21/2011.

Images by Jean-Paul Goude