Let there be three…

You can mark August 2011 as an amazing month for news in the treatment of atrial fibrillation (AF).

In this post, I will attempt to share what I have learned about the two new blood-thinning drugs, apixaban and rivaroxaban–both Factor Xa inhibitors. (Disclaimer: this is not a book chapter, rather a blog post from a regular doctor.)

First, as background, let it be said that the most important aspect of caring for AF patients is to prevent a stroke. Other goals include preventing heart failure and the improvement of quality of life through the relief of symptoms.

For decades the only means to prevent stroke in AF was to thin the blood with a drug that’s also used as rat poison, warfarin. That paradigm is changing rapidly.

As of today, we can add (assuming FDA-approval) two more medicines to the list of non-warfarin blood thinners. Dabigatran (Pradaxa) had the head start, but I strongly suspect that the Factor Xa inhibitors, apixaban and rivaroxaban, will catch up quickly. (It’s surprising that after almost a year of availability, and strong superiority data, one report of dabigatran’s market share has it at a mere six percent.)

Let’s start with an introduction of the two new drugs:

Apixaban:

The more impressive data clearly resides with the Apixaban trial. Announced today, at the European Society of Cardiology meeting (and published simultaneously in the NEJM), the results of the Aristotle trial showed that AF patients that took apixaban (5mg twice daily) suffered significantly fewer strokes and bleeds than those that took warfarin. Most striking though, was that apixaban is the first oral blood thinner that reduced the risk of death from any cause. (For more on the specifics of Aristotle, I refer you to Larry Husten’s concise summary on Cardiobrief, and Ms Sue Hughes’ piece on theHeart.org.)

Rivaroxaban:

Earlier this month, the ROCKET-AF trial (NEJM) reported that patients that took rivaroxaban 20mg once daily had fewer strokes and intracranial bleeds than those who took warfarin. Here though, the data are cloudier than the apixaban (and dabigatran (RE-LY) trial)). It’s mathematically complicated, but suffice to say that rivaroxaban can only be called non-inferior, not superior, to warfarin. Further, the risk of overall bleeding with rivaroxaban was the same—not less.

So now there are three oral blood thinners, other than warfarin, that patients with AF can take to prevent stroke.

Similarities between dabigatran, rivaroxaban and apixaban:

• Convenience: All three drugs have predictable and reliable blood-thinning properties. None affect the INR, and thus there is no need, nor means to monitor the level of blood thinning.
• Reduction of stroke: All three trials showed that AF patients who take the newer drug suffered fewer strokes compared to those who take warfarin. Though the three trials differ enough (blinded vs unblinded, low-risk vs high-risk patients) to make absolute comparisons of the three drugs impossible, the percent reduction of stroke was strikingly similar amongst trials.
• Reduction of intracranial bleeds: This, I believe, is one of the top reasons to recommend these drugs. The most catastrophic complication of blood thinners are bleeds that occur in the brain. Intra-cranial bleeds frequently cause death, or some would say worse, a persistently vegetative state. Each of these new agents dramatically (and similarly) reduce the risk of this catastrophe.
• Death rates: Depending on your perspective, you could list death rates as a similarity or a difference. If you are a Pfizer/Bristol-Myers Squibb executive (the makers of apixaban), you would argue that apixaban is the only drug that statistically reduces the death rate. But as an independent, un-sponsored commentator, I would argue that all three drugs showed strong trends to lower overall mortality.
• The role of personal responsibility: Because these agents do not affect the INR, or any readily available measure of blood thinning, doctors cannot confirm that a patient is taking the drug as prescribed. The only person who knows whether they have stroke prevention is the patient. This “trust” issue comes up when a patient requires a procedure (like cardioversion or ablation) that requires a preceding period of adequate blood thinning.
• Lack of reversal agents: None of these agents have a rapidly-acting reversal agent. This sounds scary, but in reality most patients–other than those with bleeding in the brain—can be supported (transfused) for the few hours it takes for the drug to wear off. Here lies the paradox: It’s true, in the setting of bleeding in the brain, the lack of a reversal agent is bad news. But the thing to remember is that all three drugs markedly reduce the chance of bleeding in the brain in the first place. For me, I’d take not having the bleed in the first place–rather than relying on a reversal agent.

And some notable differences:

• Overall bleeding: Apixaban is the only of the three that can boast a reduction in overall bleeding from any cause. Rivaroxaban had an equal overall bleeding rate when compared to warfarin. Dabigatran actually increased the risk of GI bleeds. In this regard, apixaban looked like a clear winner.
• Drug interactions: Rivaroxaban, and to a much lesser extent, apixaban, gets metabolized in the liver by enzymes affected by many other drugs (antibiotics, anti-fungals and anti-seizure agents, for example.) Dabigatran has no relevant drug interactions. This will undoubtedly be a Boerhringer-Ingelheim talking point. Because many AF patients also take numerous drugs, the drug interaction problem will be a concern for rivaroxaban.
• Nuisance side effects: A substantial number (10-20%) of patients who take dabigatran experience nausea, reflux, bloating and abdominal pain. Though downplayed by some, to clinicians and AF patients these are real barriers. Neither rivaroxaban nor apixaban seem to have any of these adverse effects. This could be a problem for dabigatran.
• Dosing: Thus far, rivaroxaban looks to be the least attractive of the three: less robust stroke prevention, equivalent (not lesser) bleeding and greater drug interactions. The once daily dosing of rivaroxaban may be a huge benefit. How much the convenience of once daily dosing matters remains to be seen. I think it will be significant. Take the younger AF patients not accustomed to twice-daily medications, for example. In this group, the once-daily dosing might be a deal-breaker.

The editorial in today’s NEJM concluded by saying that a new era in blood thinning appears to be emerging. No doubt this is true.

There is a lot to learn going forward. Heck, neither rivaroxaban or apixaban are yet FDA-approved.

For fun, I’m going to give you a prediction. Based on my experience with dabigatran and (multiple) reads of the data, my hunch is that apixaban looks to be the strongest.

JMM

References:

• Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation, NEJM, August 16, 2011.
• Apixaban versus Warfarin in Patients with Atrial Fibrillation, NEJM, August 28, 2011.
• A New Era for Anticoagulation in Atrial Fibrillation, NEJM, August 28, 2011.
• ARISTOTLE Study Finds the Golden Mean of Anticoagulation, Larry Husten, www.Cardiobrief.org
• ARISTOTLE: A major win for apixaban in AF, Sue Hughes, www.theHeart.org