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.