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:

Comments

  1. frank says

    thanks for taking time to explain so the lay of us can follow and understand our situation and some coming options.

  2. Verted says

    Yes, John -thanks for the good info.
    As I sit here with my usual after Pradaxa abdominal pain and severe bloating, scared to take the anti-inflammatory I need for my gouty knee, I say “bring ‘em on”.

  3. Verted says

    Yes, and regarding your comment about “Though downplayed by some, to clinicians and AF patients these are real barriers” I can tell you from my recent drug adventures, that the side effects listed as “minor” can sometimes be very debilitating and the reason some people don’t comply with a medication routine. It’s especially true for patients with poly-pharmacy, where all of the “minors” add up to a big overall “major”. I have asked one physician in the past, who was downplaying my report of difficulty with side effects to a drug, “Have YOU ever personally taken this?”. After he answered no, I calmly asked him politely to not dis-believe me until he had. He got the message, and we reached a good understanding. I think most us do have a feel for what is going on in our own bodies.

  4. Bob Potocki says

    Hello Dr John.
    I am the guy who sent you the euro tanks blazing bike trails link!

    June 16 I had ablation aborted due to significant bleed that could not be stopped while on Pradaxa. Replaced over 5 LITRES of blood.

    Quality EP and hospital.

    So, my question is, do any of the new drugs have antidotes?
    I am a little gunshy of any bleeding that is so difficult to reverse.

    Particularly if I bleed in an accident and the emergency room is not familiar with a new thinner and its treatment.

    Thanks for any insight.

    Bob P

    • says

      Thanks for that. It was a cool crazy video.

      No antidotes for any of these thinners. Sorry about your bleeding. Keep in mind two things: the newer thinners reduce the risk of brain bleeds–the most catastrophic. And, though they have no reversal agent, they wear off in a matter of hours.

  5. frank says

    wow…. bob it’s scary to realize that depending on when one takes a thiner med. , even if the ordinary asprine if a heavy bleeding accident happens it could be the quick, messy end for us. i’m curious as to your ablation being scheduled with pradaxa in your system. did all medical folks involved know you had recently taken pradaxa ? ( within last couple of days ). as i understand it. please correct me, somebody, if i’m wrong. pradaxa has a 12 hour half life. which i think means at the end of 24 hours it’s 75 % eliminated from the system. i suppose it’s really up to us to let the world know what meds. we’re on and the risks. and to make sure they’re aware and take our concerns seriously. another way: i read someplace to think about it as: do we stay off of thinners and take the minute by minute risk of a clot/af putting us away or the risk of an accident that results in our bleeding out. hmmm…. i think at this point i’ll chose the med. to reduce chance of stroke, then against it in case of an accident or emergency surgery.

  6. Verted says

    Out of curiosity, I’m wondering if since the newer drugs reach a full anti-coagulation level in a matter of several hours, instead of several days or weeks, like Coumadin, if therapy could switch from a fulltime regimen of anti-coagulation to an “as needed” regimen, for those who were formally, but are not currently, in afib, and take the meds as a precaution – similar to the pill in the pocket taking of an antiarrhythmic drug at first onset of an afib episode. Would that be enough to offer protection, or do clots form and become dangerous too quickly for that to be effective?

    If it is a possibility, that could limit the possibility of a major bleed or a hemorrhagic stroke, given the lessened exposure to the drug. That means you do have to have the meds with you and available quickly, though.

    I’m going to ask my cardiologist about that at next week’s appointment

    • says

      Good idea Verted.

      The problem is that a lot of AF is not felt. We docs call this asymptomatic. And not only that, the time course of how long it takes clots to forms is not well known. It may be shorter than dogma holds.

  7. frank says

    i’m a dedicated pradaxa fan. cause , so far, thank goodness i’ve had non off the reactions some others have had. glad to have left coumadin behind. who knows where i’d be now if it was not for coumadin but pradaxa is so much easier to live with. which takes me to just taking it when one “feels something coming on ” i’ve had the same feelings but quickly dispelled them on my own. we buy all kinds of insurance in case something happens. thinners to me are not in case something happens but to keep something from happening. i want to be true to the times and dosage. but i’d be very interested in your cardios views, about as only when need.

  8. Allan says

    Reversing agents might be on the way. See the pdf below:

    http://emcrit.org/wp-content/uploads/dabigatran-review.pdf

    “Although there is no specific antidote to antagonise the anticoagulant effect of dabigatran, due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity. In case of potential overdose, the feasibility of early administration of activated charcoal and subsequent charcoal filtration are undergoing preclinical evaluation.”

  9. Verted says

    Having known two people who died or had a stroke from coumadin related major hemorrhagic bleeds, and at least one who had a major eye problem from it , and knowing no-one in my circles who has had a stroke – either in afib or not, I’m very concerned about a lifetime regimen on any anti-coagulant. In looking at the available statistics, it’s hard for me to see that there is much difference in risk between being anti-coagulated or not. Drilling down, it appears on the surface at least that the risks of a major problem are almost the same – the difference being in the type of problem.

    I wonder what real life risks and results are actually seen in clinical practice? Any comments?

    If the newer drugs do indeed address this problem, I know I would feel more comfortable taking them. I worry a lot about things like working with power tools, or slipping at the pool and hitting my head. It’s a real concern for many, especially if it forces you to give up a major life joy or activity..

    As always, I’m just plain curious and questioning. . . . .