Coumadin Replacements in Trial — Dabigatran and Rivaroxaban
January 5, 2009 7:21 AM CT
If you’re on Coumadin, you’re probably interested in the coming replacements for it. In part 2 of our Coumadin series, Dr. Manish Shah, Electrophysiologist at Washington Hospital Center in Washington, DC, answered our questions about blood thinner drugs in trial to replace Coumadin.
In this video, he talks about the clotting cascade and the two categories of drugs—thrombin inhibitors and Factor Xa (10a) inhibitors—that are potential replacements for Coumadin. He discusses and compares dabigatran, a thrombin inhibitor, and rivaroxaban, a Factor Xa inhibitor.
While neither of these drugs is currently available in the United States, dabigatran is available in Europe and Canada.
Also watch Part 1 of our Coumadin Series: Do You Need Coumadin: Your CHADS2 Score
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About Dr. Shah: Dr. Manish H. Shah is Associate Director of Cardiac Arrhythmia Research at the Washington Hospital Center in Washington, D.C., and Assistant Professor of Medicine at Georgetown University School of Medicine. Dr. Shah comes to Washington Hospital Center from the Johns Hopkins Hospital in Baltimore where he completed a five-year fellowship in Clinical Cardiology and Clinical Cardiac Electrophysiology. He served as Hopkins’ Chief EP fellow for 2007-2008. Prior to his training in Baltimore, Dr. Shah completed an internship and residency at the Harvard Medical School Brigham and Women’s Hospital in Boston.
There has been some excitement more recently about some novel agents that may be easier to take for patients that will also cause the same level of blood thinness and will provide them with the stroke risk reductions that Coumadin provides them.
One way for us to begin to understand this is to understand a little bit about how our blood clots. We can see that this is a simplified version of what’s called the clotting cascade, which is a brief diagram that really shows us that we have some chemicals or molecules in our blood that allow for blood to clot. The major transition is from one molecule, which is called Prothrombin, in its transition to this molecule, called Thrombin.
This agent, Thrombin, is really one of the critical molecules involved in the clotting cascade. So, once we have active Thrombin formation that actually will allow this small product here, called Fibrinogen, to form a clot.
There have been several drugs that have been designed to target either this agent, Thrombin, or this agent, which happens to be called Factor Xa (10a). By doing that we can decrease the amount of Thrombin that is produced. We have drugs that either specifically decrease the amount of Thrombin that is produced, or we have drugs that will specifically inhibit this Thrombin molecule. Those are really the two novel agents that are coming into practice in the next several years that will provide an alternative to Coumadin use.
Once again, there are two medications, the Thrombin inhibitor, and that medication is called Dabigatran it is a long name and the Factor Xa inhibitor, called Rivaroxaban, which is another long word.
There was one previous agent that was a precursor to Dabigatran, which was taken off the market several years ago because it had some problems with liver toxicity as well as an increased incidence of heart attacks. For that reason the FDA, the Federal Drug Administration, took this drug off the market several years ago.
This other medication, Apixaban, is one that has not had a positive trial yet to show its usefulness in comparison to Coumadin and that is why I have made it smaller here.
The two agents that I would like to focus on are the two oral, meaning that we take them by mouth, medications that can cause blood thinning.
When we compare these two agents, Dabigatran and Rivaroxaban, we can find that in terms of where they are in their staging is that most drugs have to go thru a phase one, a phase two, a phase three and a phase four of clinical trials to evaluate not only their safety, but also their efficacy, or how good those drugs are. These medications have been compared to Coumadin or other agents like Lovenox, which is an injectable blood thinner agent.
Both of these medications have either completed the phase three, in the case of Dabigatran, or are in the enrollment for phase three for treatment of atrial fibrillation in terms of stroke risk reduction.
The nice thing about these medications, as shown here in the dosing frequency, is that these medications are taken by mouth either once a day, for the case of Rivaroxaban, or twice a day with Dabigatran.
For the case of Dabigatran, it really has very few drug-drug interactions. That is one of the major problems with Coumadin in that it often interacts with several of the medications that we also use to treat atrial fibrillation, such a Amiodarone or Digoxin. Several antibiotics or antifungal agents can also cause some problems with Coumadin use and we have to be careful about monitoring the levels of our blood thinness when we take both of those agents simultaneously.
So, the nice thing about Dabigatran is that it actually does not have many of the drug inhibitions, or the drug-drug interactions, that we worry about it does have one common medication, proton pump inhibitors, which are medications like Prilosec or Nexium that are two of the trade names that we commonly use to treat patients with gastroesophageal reflux disease, or reflux. So that is one medication that we will have to make sure that we adjust the dose of Dabigatran for.
The alternative agent, the Rivaroxaban, does have similar drug-drug interactions to Coumadin. It is actually metabolized in the liver and because of that we will also have to be careful with that medication like we are careful with Coumadin.
One of the drawbacks to both of these medications is that, unlike Coumadin, there is no antidote for it. In the case that if you are in a car accident while taking these medications, we have an easy way to reverse the effects of Coumadin. But we unfortunately, as of now, do not have an easy way to reverse the effects of the blood thinning with either of these two new medications.
I suspect that Dabigatran should be presented to the Federal Drug Administration within the next year to two years and will likely be considered for approval at that time. There has been a large trial that has been run with Dabigatran where in that setting those patients who are on that medication there are almost 18,000 patients who are taking the medication did not have any problems with the liver toxicity. There have been no safety alerts with that trial even though the official results have not been published yet. That signals that there is a good chance that the FDA will approve that drug in the next one to two years.
Lastly, in terms of monitoring, neither of these medications will need the frequent blood checks as we do for Coumadin, which is something that most patients will be excited about.
That is about all we know about these two medications. I think that they are both very promising alternatives to Coumadin therapy, and we will see in the next few years. We are excited about getting our hands on them, too, once they become available.