A New Option in Stroke Prophylaxis?

Mark J. Alberts, MD


November 03, 2011

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Editor's Note:
This video commentary was recorded prior to the US Food and Drug Administration's November 4, 2011 approval of rivaroxaban for the prevention of stroke in patients with nonvalvular atrial fibrillation.

Hello and welcome to this Medscape Stroke Update. My name is Mark Alberts. I am a neurologist and Director of the Stroke Program at Northwestern University in Chicago, Illinois.

Today I would like to talk to you about rivaroxaban, an oral anti-Xa agent that has been studied for the prevention of stroke and systemic emboli in patients with atrial fibrillation (AF). The key study that looked at rivaroxaban was the ROCKET AF study, recently published in The New England Journal of Medicine.[1] The outcome of ROCKET AF was positive for the primary endpoint of noninferiority of rivaroxaban vs warfarin for stroke and systemic embolization.

If you look at the data and results in more detail, you find that most of the efficacy of rivaroxaban was driven by a reduction in systemic emboli and a reduction in hemorrhagic stroke in the rivaroxaban group vs the warfarin group. There was no real difference in terms of prevention of ischemic stroke with rivaroxaban vs warfarin, which is somewhat unusual considering what other studies of these new agents have shown. On the positive side, rivaroxaban was certainly safer than warfarin, with a reduction in major bleeding, particularly intracranial hemorrhage, compared with warfarin.

The US Food and Drug Administration (FDA) evaluated these data very recently. The FDA's internal scientists had some concerns about rivaroxaban and the design of the ROCKET AF study because, overall, less than 60% of the patients in the warfarin group were not within the therapeutic range, as measured by INR. In other studies, 65% or 67% of patients taking warfarin were in the [therapeutic] range of an INR of 2.0 to 3.0. The FDA was also concerned because of the complications of the study design of ROCKET AF. Some analyses were conducted on the intention to treat population, some were conducted on the protocol treatment, and others were conducted on the on-treatment patient groups. The study design made the overall analysis somewhat complicated.

The FDA was also somewhat concerned that patients who discontinued rivaroxaban appeared to experience some sort of rebound effect, where their risk of having an ischemic event was higher after discontinuing treatment. Honestly, this may just be an artifact of the way the study was designed, how these events were allocated in relationship to stopping the study medication, and having these events assigned to the rivaroxaban group vs the warfarin group, depending on how patients were randomized.

Thus, the study design made it very complicated to understand whether this increase in events was really related to a rebound effect or to stopping the study medication, wih a background effect of patients being unprotected for some certain period of time. The FDA scientists had concerns, but after looking at all of the data, the FDA Advisory Committee thought that rivaroxaban did meet the noninferiority analysis and that it should be approved.

Where do we stand at the end of the day? Frankly, we don't know. We do not know what the FDA is going to do. Usually they do take the advice of their advisory committees but not always. Clearly, interpreting some of the ROCKET AF data is somewhat complicated and complex. This has to be understood in the context of dabigatran being approved about a year ago and now there with a lot of experience with that drug, and the recent data on apixaban, another oral anti-Xa agent, which certainly appeared to be as safe, if not safer than warfarin, and more efficacious than warfarin.

We will have to see what happens, but I think it is safe to say that we have additional oral anticoagulant options above and beyond warfarin, and possibly above and beyond dabigatran, that we can use to prevent strokes and systemic emboli in patients with AF.

Thank you very much for tuning into this Medscape Stroke Update.


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