Last week the FDA finally approved apixaban (Eliquis) for the prevention of stroke in patients with non-valvular atrial fibrillation. I use the words ‘finally approved’ because the markedly positive ARISTOTLE trial was published 15 months ago in the New England Journal of Medicine. The long delay was mysterious.
On paper, apixaban looks to be the strongest of the three warfarin-replacement agents (dabigatran (Pradaxa) and rivaroxaban (Xarelto) being the other two). Here is an old post of mine that generally outlines the three.
In the ARISTOTLE trial, (nicely covered here on theHeart.org) apixaban at a dose of 5 mg twice daily was compared to warfarin in 18,000 patients. Apixaban statistically bested warfarin in three major categories:
- Lower rates of stroke*
- Lower rates of overall bleeding, with much less intracranial bleeding.
- Improved mortality.
The asterisk on stroke reduction is the major criticism of apixaban. Let me explain: Apixaban did indeed lower the overall rate of stroke, but the reduction was driven by fewer hemorrhagic strokes. Ischemic strokes–those caused by clots or blocked blood vessels–were similar in both groups.
This phenomenon may be specific to Factor-Xa inhibitors, as it was also seen with rivaroxaban in ROCKET-AF. Dabigtran, on the other hand, reduced both types of strokes.
Critics of novel anticoagulants will view this subtle finding as a knock against Factor-Xa inhibitors. They say an anticoagulant should work by reducing clot-related strokes. And no doubt, Boerhinger-Ingelheim (makers of dabigatran) will use this as a talking point to favor dabigatran.
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
Of course, for you or me, as a patient, what matters most is not the mechanism of brain injury; it’s simply not having one. Overall stroke reduction seems to be the most important measure.
My take home:
This is a big development. Apixaban looks strong. It’s the only drug of three that statistically lowered mortality–the ultimate metric.
Novel anticoagulants really started to take off in 2012. Most of the growth was with rivaroxaban. The once-daily drug is well-tolerated. Unlike dabigatran, rivaroxaban does not cause GI symptoms. This difference doesn’t seem like much in the pages of the NEJM, but in the real world, it’s huge. The other tailwind for rivaroxaban was the “bad drug” commercials knocking dabigatran. Patients see these ads, and they have had an effect.
Assuming apixaban is priced competitively, I see it moving in immediately and being a major player. Its displacement effect on the other two agents is hard to predict. On the one hand, you could argue that doctors will choose apixaban over dabigatran because of its lack of GI side effects and over rivaroxaban because of its superior data. But on the other hand, another warfarin-replacement agent will surely grow the pie larger.
A final issue: One area that comes up a lot is what to do with anti-coagulants in the time before and after AF procedures, like cardioversion and ablation. Here, we have tons of data with warfarin, a little with dabigatran and essentially none with rivaroxaban and apixaban. Given that many AF patients get started on these drugs with an eye towards rhythm-control, this is an important topic to pay attention to. I look forward to hearing more about the peri-procedural safety of the Factor Xa inhibitors.
It’s an exciting time in the treatment of atrial fibrillation.
