This post is authored by Christopher P. Cannon, MD, FACC, editor-in-chief of the Science and Quality section of CardioSource.org and an associate physician in the Cardiovascular Division at Brigham and Women's Hospital in Boston. He also is an associate professor of medicine at Harvard Medical School and a senior investigator of the Thrombolysis in Myocardial Infarction (TIMI) Study Group.

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For the first time in over 50 years – we have a new oral anticoagulant to use in place of warfarin!  This past week, the FDA approved the oral thrombin inhibitor dabigatran (Pradaxa) for the prevention of stroke or systemic embolism. The approval was based on the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, which found that dabigatran, an agent that does not require monitoring of the INR, was as safe and effective, and at the 150-mg twice daily dose, actually superior to warfarin.

Although few people were surprised by the approval of the drug, what was surprising was that only one of the two doses tested in the RE-LY are the doses that the FDA approved. The RE-LY trial tested the effectiveness of 110- and 150-mg twice daily doses. However, the FDA approved only the 150-mg dose (with 75 mg pills also available) – but not the 110 mg dose.

I queried the FDA, and they wrote back to me saying they would soon post an explanation of their rationale. They did explain the 75-mg dose (which wasn’t included in the RE-LY trial) as wanting a treatment option for patient with severe kidney impairment.

SO – what about the 110-mg b.i.d. dose? This dose was seen to be as effective as warfarin. The topline result from RE-LY found that dabigatran 110-mg vs. warfarin had a relative risk of 0.91 and 95% confidence interval [CI] of 0.74 to 1.11 (p<0.001) for noninferiority. So the trial has a pre-specified endpoint and analysis plan, and meets it with p<0.001, and yet FDA doesn’t approve it? I honestly don’t understand. The key is that there is a lower rate of major bleeding: 3.36% per year for warfarin and 2.71% with 110-mg of dabigatran (p = 0.003) and a significantly lower rate of intracranial hemorrhage! So, we have a drug regimen that is equivalent to our current treatment – but safer, and doesn’t require monitoring. With the FDA’s key focus on safety, how could they not approve this safer dose of the drug?

Thoughts on Why
For now we don’t know why. The agency could say that the 150-mg dose is better, so there is no need to approve a dose that is not as efficacious, but I would counter that is true for a lot of medications. Atorvastatin has an 80-mg dose that is proven to be better than 10-mg, but all doses are still on the market!

Some have said that because it was an open-label trial (actually partially blinded to the dabagatran dose) that this makes it harder to be 100% sure that there was not bias in assessing bleeding. But that really doesn’t hold either since the dose of dabigatran was blinded and, thus, neither the physicians nor patient knew which dabigatran dose they were getting and yet the FDA approved the higher dose. We will learn more soon, but I hope that this dose can continue to be discussed and ultimately approved.

The reason is: I think about all the patients I have treated in the past month with AFib – they are all very old, and most have risks for bleeding. For example, I admitted a patient recently for AFib and bradycardia. He is over 90, has trouble walking and falls often. He has been treated with warfarin, but the team admitting him was fearful that he might fall and get an intracranial hemorrhage. Wouldn’t it be nice to have a safer dose for this patient? I could name many other patients just like him – probably half of my Afib patients have stories like this where having a safer alternative to warfarin would be the optimal choice for therapy.

FDA apparently will soon offer some insight, but I hope that the 110-mg dose will continue to be discussed. It is available in Europe – and one physician from Turkey spoke to me yesterday at the Cardiometabolic Health Congress, where he said has over 100 patients on the 110-mg dose – and he has been very happy with their clinical course. I just hope that all the trial nit-picking can end and people look at the big picture and see this new treatment option for what it is worth – a major new advance in treating patients with AFib.

Why do you think the FDA did not approve (at least yet... people know I am ever the optimist) the 110-mg dose?

[youtuber youtube='http://www.youtube.com/watch?v=JOYunU9LXx0']

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