From to ximelagatran to dabigatran - how far have we come?

I still remember the days when people thought ximelagatran was going to change the world of anticoagulation. The days of the Coumadin (warfarin) clinics seemed numbered. People who would require frequent INR checks would no longer have to get poked with needles. They could eat all the green vegetables they desire. They would no longer take rat poison. Then, the sad news about ximelagatran hit the news. Ximelagatran (proposed trade name Exanta) was not going to be approved by the FDA because of liver toxicity. That was 2006.

Fast forward now to 2010 and we see that the FDA advisory committee (not the FDA, but the FDA advisory committee) unanimously today recommended the approval of dabigatran. This means that the FDA will probably approve dabigatran in the near future, but we still need to wait and see. Meanwhile, a host of other new anticoagulant drugs are waiting in line.

So what are these new oral anticoagulants? Let's see what Wikipedia has to say:

• Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin. Agents in the pipeline include: dabigatran, melagatran (and its prodrug ximelagatran), and others.
• Direct factor Xa inhibitors ('xabans') are a class of antithrombotics which act directly upon Factor X in the coagulation cascade, without using antithrombin as a mediator. Agents in the pipeline include: rivaroxaban, apixaban, edoxaban, otamixaban, and others.

The landscape of oral anticoagulation is about to change if these new oral agents get approved by the FDA. What role will Coumadin (warfarin) play in all of this? Will we look back in 20 years and wonder how we managed patients on a drug like Coumadin? Will these new anticoagulants stand the test of time? What will happen to all the injectable agents like enoxaparin (Lovenox), certoparin (Sandoparin), tinzaparin (Innohep), dalteparin (Fragmin), and others?

Physicians will need to be more familiar with the pharmacological profiles (half-life, interactions, etc.) as they choose among the myriad of available agents when they're treating patients with atrial fibrillation, DVT, or PE. Hospitalized patients at risk for DVT may no longer need to suffer from multiple injections if they simply need to take a pill. These emerging agents may also be used for patients who have artificial heart valves, those who have other types of hypercoagulable disorders, and more.

Back in 2006, we thought we were going to see a revolution in anticoagulation management, but it didn't happen. Now, in 2010, it appears like we may truly be looking at a new era.

Coumadin and Pharmacogenetics

I know many people who have to take warfarin (Coumadin) because they have a history of venous thromboembolism or VTE. Blood clots can be deadly. Coumadin isn't an easy drug to take. The effects of the drug can really vary based on what you eat, especially if you eat anything that is high in vitamin K like green leafy vegetables. Coumadin acts by blocking the actions of vitamin K (it's often called a vitamin K antagonist).

The The International Warfarin Pharmacogenetics Consortium researchers have found that "the use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach." Sounds pretty interesting, doesn't it? Take a look at the New England Journal of Medicine (NEJM) article here if you'd like to read more about this interesting pharmacogenetic algorithm.

What's Happening at the FDA with Rivaroxaban?

Last month, the FDA panel (which included clinical experts) voted 15 to 2 in favor of rivaroxaban (which may get marketed as Xarelto by Bayer and J&J if it receives FDA approval). What's going on at the FDA this month?

Speaking of new anticoagulants, Pradaxa or dabigatran etexilate is another agent that may be nearing approval. This drug is made by Boehringer Ingelheim and has received maketing approval by the European Commission. Unlike rivaroxaban (which is an oral factor Xa inhbitor), dabigatran is an oral direct thrombin inhibitor (DTI). Both are oral pills and both may someday replace warfarin (Coumadin) if they receive FDA approval for anticoagulation.

There's always a bleeding risk associated with an any anticoagulant drug, so the big question is whether the risks outweigh the benefits. Let's hope that these drugs don't follow the same fate as ximelegatran (Exanta).

Rivaroxaban to be Reviewed by the FDA Panel on March 19

March 19 is match day for 4th year medical students. It's also the day when the FDA Panel is supposed to review the anticoagulant rivaroxaban (also known as BAY 59-7939 or Xarelto). It is an oral, direct Factor Xa inhibitor (I don't think I'll ever forget that coagulation cascade diagram that I learned in medical school). If approved, this drug could shut down all those coumadin (warfarin) clinics out there that monitor blood INR in people taking this vitamin K antagonist. Rivaroxaban would not require any blood monitoring. Plus, all those home INR tests manufacturers would need to look for something new to do.

I think everyone is wondering how the FDA will react to this new medication. If approved by the FDA, rivaroxaban will be sold in the US for short-term use as a prophylactic anticoagulant for patients undergoing knee- and hip-replacement surgeries. I'm sure the drug manufacturers will go for additional indications later on. Rivaroxaban is manufactured by Bayer and will be marketed by Ortho-McNeil Pharmaceutical which is a Johnson & Johnson group.

Are the Days of Coumadin Over?

I know someone on a personal basis (not a patient) who used to take Coumadin for recurrent DVTs. His INR used to go all over the place because he would alter his diet and start new medications that often interacted with Vitamin K. Back in those days, physicians used to dream about a magic pill that didn't require any INR monitoring and that would provide optimal anticoagulation to prevent DVTs. Many people are now wondering, "Is rivaroxaban/BAY 59-7939/Xarelto the first pill that will replace Coumadin and eliminate routine INR monitoring?" I'm very eager to see how other oral factor Xa inhibitors will compare. Is factor Xa inhibition the ideal mechanism? What about factor IIa? Direct thrombin inhibitor? The world of pharmacology is changing so rapidly that it's impossible to keep up with all these changes.

Rivaroxaban submitted for FDA approval

What will happen to all those patients on coumadin (warfarin) if we get a new pill that requires no INR monitoring? Well, rivaroxaban (Xarelto®) may be that first pill in the USA. Rivaroxaban has been submitted for FDA approval. It acts by inhibiting factor Xa, so there is no INR to check since it does not work like warfarin (that inhibits vitamin K-dependent clotting factors).

What will happen to all those Coumadin clinics out there? What about all those fingerstick INR machines? Labs processing those weekely INR checks?

There was a lot of excitement several years ago with the development of Ximelagatran (Exanta). Live toxicity ended the development of that drug in the USA.