October 20th, 2010

Dabigatran Is Approved

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

There can only be one cardiology story to discuss today.

Tuesday, the FDA approved dabigatran (Pradaxa), an oral anticoagulant for the prevention of stroke in atrial fibrillation.

Previously, the only drug approved to prevent stroke in patients with AF was warfarin. Despite the well-known, sound scientific data in support of warfarin for the prevention of stroke — arguably one of life’s most tragic chapters — the  adverse effects of warfarin precluded its unanimous acceptance.  From the beginning, warfarin was known to be the active ingredient in rat poison; this has been (and still is) a tall hurdle to overcome. Moreover, everyone seems to know someone who was “killed” by warfarin.

And its history is not warfarin’s only weakness. It is a tricky drug to use. Moderating blood thinness requires a motivated patient and a motivated health care system. For example, even rigorous clinical trials — with their armies of clinical specialists—only manage a TTR (time in therapeutic range) of 60%-70%.  Finally, we all know of the many unfavorable interactions — drug-drug, drug-diet, and even drug-DNA (variable metabolism) — of warfarin.

So it is with great excitement that the medical community welcomes dabigatran, the first warfarin substitute. Congratulations Boehringer Ingelheim, it is your field of dreams, at least for the moment.

Few U.S. clinicians have any real-life experience with dabigatran.  We will learn together. Without doubt, there will be great initial fanfare; I have already received two letters from Boehringer inviting me to be a featured speaker. It’s just a hunch, but I think the dabigatran launch will likely make the Multaq carnival look like a mere parish picnic.

For use of dabigatran in the real-world, outside the cocoon of carefully controlled clinical trials, much remains to be learned. Answers to questions like:

  • In the RE-LY trial, dabigatran was used twice daily.  Patients often find it difficult to remember their second daily dose when not experiencing symptoms.  Will adherance issues limit dabigatran’s effectiveness? Will once-daily dosing work as well as twice daily?
  • In RE-LY, 12% of dabigatran recipients reported GI discomfort (dyspepsia), a rate double that for warfarin. Will this be clinically significant?
  • Does dabigatran increase the risk for MI (heart attack)?  In RE-LY, patients in the dabigatran cohort were at a slightly higher risk for MI.  In the 150-mg (higher-dose) dabigatran group, the P value barely reached statistical significance. (Translation: we don’t think dabigatran increases the risk for MI, but we are not quite sure yet.)
  • Dabigatran is cleared mostly by the kidneys.  Therefore, patients with chronic kidney disease will be at increased risk for bleeding due to higher blood levels of the drug. Dosage adjustments will need to be made, and patients’ with severe kidney disease will not be candidates for dabigatran.  Use of renally excreted drugs is challenging outside of clinical trials.  How will this sort out with widespread use of dabigatran?
  • Will dabigatran be useful in many other warfarin-treated diseases?  Things like mechanical valve protection, stroke prevention in LV aneurysms, and hypercoaguable states (like Factor V Leiden)?  Probably the answer will be yes.  We’ll see.
  • But the real elephant-in-the-room is cost.  Who will bear the brunt of the extra cost?  How much extra out-of-pocket cost will patients tolerate to free themselves from “rat poison,” and to reap the benefits of dabigatran’s improved stroke prevention and lower risk of intracranial bleeding?  (The cynic in me says, not that much.)

One thing remains certain: the excitement over dabigatran’s addition to AF therapeutics will surely be great for AF doctors and patients alike.

It will be a fun ride.  Stay tuned.

Comments are closed on this post, but please join the conversation at our Dabigatran Resource Round-Up.

2 Responses to “Dabigatran Is Approved”

  1. There are at least 3 other agents (oral factor Xa inhibitors) that are in Phase III trials as anticoagulants vs warfarin in atrial fibrillation and may appear on the scene within the next several years.

    Rivaroxaban – ROCKET-AF (to be presented at the AHA meeting in November)

    Apixaban – ARISTOTLE

    Edoxaban – ENGAGE AF – TIMI 48

    Competing interests pertaining specifically to this post, comment, or both:

  2. Regarding the cost issue: If dabigatran proves to be as efficacious in real-life practice compared to warfarin at the 150 mg BID dose, then there should be no issue with cost at the level of the insurance companies. The insurance companies should realize that the monitoring involved with warfarin as well as the incidence of hospitalizations due to problems with warfarin are more costly than a twice daily dose of a DTI. Then again, they don’t recognize the difference between Cordarone and Multaq in terms of the toxicity profiles. I am curious to see what will transpire.