CardioExchange Archive

CardioExchange welcomes this guest post reprinted with permission from Dr. Westby Fisher, an electrophysiologist practicing at NorthShore University HealthSystem, Evanston, IL, and a Clinical Associate Professor of Medicine at University of Chicago’s Pritzker School of Medicine. This piece originally appeared on his blog, Dr. Wes.

A new era of nonvalvular atrial fibrillation management has arrived.

Tuesday, the FDA approved the first new anticoagulant in fifty years: dabigatran, marketed by Boehringer Ingelheim Pharmaceuticals under the trade name Pradaxa, for stroke prevention in patients with nonvalvular atrial fibrillation. The move was widely anticipated after the drug’s unanimous 9-0 FDA advisory panel recommendation for approval a month ago. The drug will be available in 75 milligram and 150 milligram dosages and is taken twice daily.

Patients at high risk for thromboembolism from nonvalvular atrial fibrillation are candidates for the drug, including patients with previous stroke or transient ischemic attack, a left ventricular ejection fraction of less than 40%, New York Heart Association class II or higher heart-failure symptoms within 6 months before screening for the medication, and age of at least 75 years, or age 65 to 74 years plus diabetes mellitus, hypertension, or coronary artery disease.

Patients who should NOT receive the drug include patients with the presence of a severe heart valve disorder, stroke within 14 days or severe stroke within the last 6 months, a condition that increases the risk of hemorrhage, a creatinine clearance of less than 30 mL per minute, active liver disease, or pregnancy. Patients taking quinidine should not take the medication because of a significant drug interaction.

The drug does not typically require measurement of blood thinning levels (prothrombin times expressed as an international normalized ratio (INR) of clotting time to a standard clotting control).

The approval was based on the prospective, randomized RE-LY trial recently published in the New England Journal of Medicine that compared the safety and efficacy of two doses of dabigatran (110 mg and 150 mg twice daily) to conventional warfarin (Coumadin) therapy in 18,113 patients and showed that:

dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage.

It should be noted that the FDA did not approve the lower, 110-mg dose of the medication.

The drug’s most common side effect was dyspepsia (GI upset), but liver enzyme elevations were not different from those seen with warfarin.

The questions now are two: when will it be available? and how much will it cost?

Typically it takes about 3 to 6 months to finalize product packaging, labeling and distribution after a drug is approved.  As far as price goes, my bet is that it’s going to cost about ten times the cost of warfarin. I’d estimate $6 to $9 per day. (One writer calculated the cost of dabigatran in the U.S. based on its cost in Canada at approximately $7,000 to $9,000 per patient-year — four to five times the cost of warfarin, despite the increased physician and laboratory costs required to monitor the INR). A researcher from the RE-LY trial countered:

It should also be kept in mind that total direct and indirect costs for management of anticoagulation with warfarin far exceed the cost of the drug. In a recent study, the direct costs during the first year of anticoagulation with warfarin in primary care were calculated at Swedish krona 16,244, corresponding to U.S. $2,230. This does not include expenses to patients for travel to the laboratory, lost time from work, or an accompanying caregiver.

I suspect it will be hard for insurers to swallow the cost of this drug at first, and coverage may not be immediately available, but hopefully the superior convenience and stroke prevention will justify the drug’s initial price. Fortunately, other thrombin inhibitors will soon compete in price with dabigatran, shortening its exclusive first-to-market reign.

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

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.