Dabigatran is approved

There can only be one cardiology story to report today.

Earlier today, 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 unfavorable adverse effects of warfarin precluded its unanimous acceptance.  From the beginning, warfarin was known as 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 history is not warfarin’s only malady. It is a tricky drug to use. Moderating the degree of blood thinness requires a motivated patient and health care system. Take as an example that 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 drug-drug, drug-diet, and even drug-DNA (variable metabolism) interactions of warfarin.

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

Few US 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 the dabigatran launch will likely make the Multaq carnival look like a mere parish picnic.

In using dabigatran in the real-world, outside the cocoon of carefully controlled clinical trials, much remains to be learned.

Questions like:

  • In the RE-LY trial, dabigatran was used twice daily.  When not symptomatic, patients often find it difficult to remember their second daily dose.  Will compliance limit dabigatran’s effectiveness? Will once daily dosing work as well as twice daily? 
  • In RE-LY, 12% of dabigatran patients reported GI discomfort (‘dyspepsia’). This was double the rate of warfarin. Will this be clinically significant?
  • Does dabigatran increase the risk of MI (heart attack)?  In RE-LY, patients in the dabigatran cohort were at slightly higher risk for MI.  In the 150mg (higher dose) dabigatran group the p-value barely reached statistical significance. (Translation: we don’t think dabigatran increases the risk of MI, but we are not quite sure yet.)
  • Dabigatran is cleared mostly by the kidneys.  Therefore, patients’ with chronic kidney disease (CKD), by virtue of higher blood levels of the drug. will be at increased risk for bleeding. Dosage adjustments will need to be made, and patients’ with severe kidney disease will not be candidates for dabigatran.  Outside of clinical trials, using renally-excreted drugs is challenging.  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 will be 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 brought by dabigatran’s addition to AF therapeutics will surely be great for AF doctors and patients alike.

It will be a fun ride.  Stay tuned.

JMM

Also, my colleague, Dr Wes Fisher, has written an informative piece on Dabigatran.

Comments

  1. Steve Parker, M.D. says

    I read that the cost of dabigatran may be the range of $8-12 a day; let's just round off to $3600/year. I doubt coumadin is anywhere near that, but don't know for sure.

    Many heart patients are also taking Plavix. UpToDate.com suggests to avoid concommitant usage with Plavix (clopidogrel).

    But, yes, it's an exciting development.

  2. Dab Hackam says

    John I think most misunderstand p values. When something has a p value of less than .05 it does not magically mean it’s the “truth”. That was connoted in what you wrote “we don’t think dabigatran increases the risk of MI, but we are not quite sure yet”. One has to take into account everything we know about this drug including earlier phase trials and, most importantly, ongoing studies in ACS patients. Ximelagatran was also (falsely) accused of increasing MI rates, but it actually reduced them in ESTEEM in a post-MI population (on top of aspirin and other therapies).
    It is remarkable how it’s become the case that p.05 means “no”. This is a complete misunderstanding of statistics as applied to clinical trials and experimentation.

  3. Hackam says

    Sorry. last statement should have read, it's remarkable how it's become the case that a p value more than .05 has become "no" and less than .05 has become "yes".

  4. DrWes says

    John-

    Maybe one more question: How will it affect surgical procedure planning? How long off it before a procedure, etc. These issues still need to be sorted out as experience with the med is gained.

  5. Anonymous says

    Oh my goodness! I am so excited about this drug even those with Factor V Leiden and Antiphospholipid Antibody Syndrome cannot use it yet. I have been on Warfarin for the last four and a half to five years (since I was about 22). Warfarin has caused so many problems for me from a diet standpoint. Not to mention how badly controlled the levels are. I go in about once a week right now, and as someone who was young when they started it and someone who is still young, this drug has been a total pain in the rear! I don't want a stroke, but I would like some freedom from Warfarin. This is so exciting to see what's to come! I can't wait!

  6. Anonymous says

    The cost came in at $6.75/day–far less than the $180/day for the generic for Lovenox (enoxoprin). My husband has had 3 pulmonary emboli over the last 10 years due to Factor V Leiden's. When they started him on warfarin this time he went into anaphylactic shock and nearly died. Unfortunately, he turns 65 next month and his Medicare Advantage plan will not approve Pradaxa until it is added to Medicare's formulary (even though it is FDA approved). Susan Crawford PhD, RN