July 14th, 2011

Rivaroxaban: The Next Non-Warfarin Oral Blood Thinner

John Mandrola is a cardiac electrophysiologist and blogger on matters medical and general. Here is a recent post from his blog, Dr John M.

The unrelenting epidemic of inactivity and excessive eating wreaks havoc on more than just the heart and blood vessels. Lugging around extra weight also breaks down the joints and back. For evidence, look no further than the waiting room of any orthopedist: the people waiting for joint replacements look the same as those waiting to see the heart doctor.

Bone doctors and heart doctors must deal with the problem of stasis (pooling) of blood in low-flow parts of the circulation. After joint replacements, blood can clot in the veins of the immobile lower extremities, and in atrial fibrillation (AF) clots may form in the non-contracting left atrium. Using blood-thinning drugs helps to prevent complications in both scenarios. Until 2010, having thin blood meant enduring a sharp needle, or taking warfarin.

The good news for both patients and doctors is that the number of oral blood thinners in the U.S. recently expanded from two (warfarin and dabigatran) to three possibilities.

Last week, the FDA approved once-daily rivaroxaban (Bayer and Johnson & Johnson call it Xarelto) for the prevention of venous blood clots — VTE or venous thromboembolism — in the setting of hip- or knee-replacement surgery.

This highly specific indication gets the 10-mg dose of rivaroxaban on the market.

But what’s far more anticipated is the (likely) approval of the 20-mg once-daily dose of rivaroxaban for the prevention of stroke in patients with nonvalvular AF. The FDA will meet in September to consider approving rivaroxaban for this purpose.

I see little reason to believe that the higher dose of rivaroxaban will not be approved.

The stroke-prevention data on rivaroxaban are quite strong. The ROCKET-AF trial randomized (in blinded fashion) more than 14,000 high-risk AF patients to either a single daily dose (20 mg) of rivaroxaban or warfarin. The results were clear: AF patients who took rivaroxaban had fewer strokes and far fewer serious brain bleeds. (Very nice additional coverage of the Rocket-AF trial can be viewed on these posts at TheHeart.org and Cardiobrief.)

As the second non-warfarin blood thinner approved, rivaroxaban shares many similarities with dabigatran:

  • Neither needs INR monitoring;
  • Neither has means to measure the degree of blood thinning — Doctors cannot confirm that patients are taking the drug as instructed, only the patient knows;
  • Neither requires patients to eat a special diet;
  • Both require lower dosages in patients with impaired kidney function;
  • Both have a short duration of action, and rapid onset of action — which has important implications for pre-and  post-surgical patients;
  • Neither has an antidote — but both have less risk for bleeding than warfarin.

And the differences

  • Rivaroxaban is once daily, whereas dabigatran is twice daily — this may have important implications for compliance;
  • The metabolism of rivaroxaban may cause potential interactions with other medicines;
  • Rivaroxaban thins the blood differently – As a factor Xa inhibitor, it blocks the coagulation cascade one step before the direct-thrombin inhibition of dabigatran.

And here are a few caveats and questions that come to mind:

—The Rocket-AF trial has yet to be published in a peer-reviewed journal. The data were presented in abstract form at last year’s AHA meeting. Look for a major publication soon.

—Will the slightly different manner in which rivaroxaban thins the blood prove significant? So far, the two factor Xa inhibitors, rivaroxaban and apixaban, were found to be ‘noninferior’ to warfarin, whereas the direct thrombin inhibitor, dabigatran, was shown to be ‘superior.’ Is this related to trial designs, or are they real differences?

—Rocket-AF randomized very high-risk AF patients. More than half had a previous history of stroke (or transient stroke), and the average CHADS score — a 6-point measure of stroke risk — was 3.5. As the current debate goes with dabigatran, it’s hard to know whether lower-risk patients doing well on warfarin should switch to rivaroxaban. Clinical judgement will play a large role here; so will patient choice.

—After approval of rivaroxaban, this question will naturally arise: Which is the best blood thinner? Watch for Bayer/Johnson & Johnson to posture the once-daily dosing of rivaroxaban as a major advantage to dabigatran. At the same time, Boehringer-Ingelheim will counter that dabigatran was shown to be superior to warfarin, rather than noninferior. The intricacies of the two trials (RE-LY versus Rocket-AF) will provide infinite ways to compare the two drugs, but without a head-to-head comparison, we simply will not be able to declare a winner.

—It will not be long before the fourth oral blood thinner is approved. Preliminary reports show that apixaban, another factor Xa-inhibitor, appears to be effective in reducing strokes in AF patients. Bristol-Myers Squibb and Pfizer recently announced (in a press release) that the 18,000-patient-strong ARISTOTLE trial showed apixaban to be noninferior to warfarin. An official presentation of the data awaits.

—Dabigatran has practical limitations: (1) Cost. Many patients simply cannot (or will not) pay for a drug that promises statistical benefits in the future. (2) The issue of compliance is both real and unmeasurable. I make judgements (often uneasy ones) every day on whether I think a patient can comply with taking the drug every 12 hours. Can, or did, the patient understand my instructions? (3) Dabigatran causes significant GI side effects — at minimum 10% of the time. The company says these are minor “nuisance” side effects. Maybe so, but I will tell you that sifting through symptoms of AF patients is hard enough, without adding a new pill to the mix. Is the AF patient feeling badly because of AF or because of this new pill?

For now, AF patients at risk for stroke have a choice between dabigatran and warfarin. But there will soon be other choices.

Perhaps in my career, warfarin will be one of those treatments that doctors remember with words like these: 

“…remember when we treated people with that ****”


3 Responses to “Rivaroxaban: The Next Non-Warfarin Oral Blood Thinner”

  1. David Powell , MD, FACC says:

    The summary is good. The details will be key…only RE-LY has been published. The debates will also include the quality of INR control, with initial reports showing a lower time in therapeutic range in ROCKET. The designs of the studies..with RE-LY using a prospective open-label design with blinding for event adjudification and ROCKET a double blind trial (pros and cons for both).

    ARISTOTLE met noninferiority for the primary endpoint ( intension to treat). But the company will surely want to emphasize the superiority for the secondary CV endpoint. Is that statistically kosher?

    Then there are the renal and age issues, compouded by potential drug interactions. AVEROES ( apixaban) used half dose for those meeting 2 out of 3 criteria: age, wgt, and creat cutoffs. We may need a detailed understanding of pharmacodynamics to make decisions for a substantial minority of patients, as this is an elderly group.

    At the extremes, PTT is helpful for dabigatran: a level in control (32 or less) is good for any surgery by my reading. A level more than 3x control is too high…INRs seem completely unreliable with very high levels seen on point of care assays. For the Xa inhinitors…isn’t there an anti-Xa asaay for LMWH…would this be of any utilit for the oral agents?

    Competing interests pertaining specifically to this post, comment, or both:
    I have presented for Boringer-Ingleheimer

  2. Vaughn Payne, MD says:


    I’ll take a devil’s advocate approach (which really means that I don’t have the conviction of what I’m saying):

    1. I anecdotally have seen many GI bleeds with dabigatran, and the lack of a direct reversal agent is problematic. On the other hand:
    2. If this is an issue with rivaroxaban, the (presumed) longer “therapeutic half-life” might be even more worrisome.
    3. GI intolerance with dabigatran is also an issue, and I’ve had a few patients quit taking the medicine (without telling me) because of this. I wonder if this will also be an issue with rivaroxaban. Heartburn was never a complaint of patients on warfarin.
    4. The concern of compliance with a once a day vs a twice a day medication is not verified in prior studies. Once a patient is prescribed a medication that requires thrice or four times daily dosing, the compliance rate plummets; I don’t have concern myself too much with BID dosing (think Sotalol).
    5. I think the issue of non-inferiority vs superiority to warfarin is a big one. On the surface this might be semantics, but time (may) tell if this carries clinical implications

    All that said, I enthusiastically recommend dabigatran to my new AFIB patients, and will probably do the same with rivaroxaban. For my stable warfarin patients I declare “Switzerland”, and I’m less forceful.

    Congrats on a nice review for all of us. As my age advances and my risk of AFIB increases, I’ll be even more attuned to this science.

  3. Sue Bacon, nursing says:

    IN the UK Dabigatran hs not yet got a licence (perhaps this month!) and it is interesting to hear about the experience of physicians in the US and Canada – please keeping commenting

    Competing interests pertaining specifically to this post, comment, or both:
    I have been sponsored to attend meetings etc by BI/Bayer and Pfizer and given feedback re anticoagulants to all companies when asked